CN105142730B - The eutectic mixture preparaton of cyclobenzaprine hydrochloride and amitriptyline hydrochloride - Google Patents

The eutectic mixture preparaton of cyclobenzaprine hydrochloride and amitriptyline hydrochloride Download PDF

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CN105142730B
CN105142730B CN201480024011.1A CN201480024011A CN105142730B CN 105142730 B CN105142730 B CN 105142730B CN 201480024011 A CN201480024011 A CN 201480024011A CN 105142730 B CN105142730 B CN 105142730B
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mannitol
mixture
hcl
cyclobenzaprine hcl
cyclobenzaprine
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CN105142730A (en
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M·内布洛尼
P·哥伦布
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Tonix Pharma Holdings Ltd
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Logical Knicks Pharmaceutical Co Ltd
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Abstract

The present invention relates to pharmaceutical composition and the method for preparing it, described pharmaceutical composition includes the eutectic mixture of cyclobenzaprine HCl and mannitol or the eutectic mixture of amitriptyline HCl and mannitol.

Description

The eutectic mixture preparaton of cyclobenzaprine hydrochloride and amitriptyline hydrochloride
Related application
This application claims the priority and power of the U.S. temporary patent application 61/792,757 that on March 15th, 2013 submits Benefit, by quoting its content and being openly fully incorporated herein.
Background of invention
Cyclobenzaprine or 3- (5H- dibenzo [a, d] cycloheptene -5- subunit)-N, N- dimethyl -1- propylamine are eaten by U.S. Product and drug office ratify the acute muscle cramp for treating Local Origin in 1977 for the first time.(Katz, W., et al., Clinical Therapeutics 10:216-228(1988)).Amitriptyline or 3- (10,11- dihydro -5H- dibenzo [a, D] cycloheptene -5- subunit)-N, N- dimethyl -1- propylamine ratified for the first time by U.S. food and drug office for treating depression.
Subsequent research has shown that cyclobenzaprine also effectively treats fibromyalgia syndrome, posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), generalized anxiety disorder and depression.In addition, cyclobenzaprine is as improvement sleep quality Medicament, the effectiveness as sleep intensifier or for treating dyssomnias have also been studied.However, what although FDA- ratified Therapeutic agent copes with pain and mood, have no at present FDA- approval reply it is related with fibromyalgia syndrome be disturbed sleep The treatment slept with fatigue.Can be particularly used for treating with cyclobenzaprine treatment is caused by fibromyalgia syndrome, by fiber Muscle pain syndrome deteriorates or dyssomnias related with fibromyalgia syndrome, extended fatigue, confirmed fatigue, confirmed fatigue Syndrome, sleep disturbance, psychoalgalia obstacle, chronic pain syndrome (II type), drug is given, autoimmune disease, Stress or anxiety, or the disease of disease and the disease for treating as caused by dyssomnias or being deteriorated by dyssomnias Shape.See, for example, the U.S. patent No. 6,395,788 and 6,358,944, it is incorporated herein by quoting.
With certain excipient compositions, cyclobenzaprine HCl or amitriptyline HCl active pharmaceutical ingredient (or It APIs is) stable in the pill, tablet or capsule formulation for oral administration.However, cyclobenzaprine HCl or Ah meter Have for woods HCl when taking orally and swallowing (oral or po) and slowly absorbs.In order to accelerate to absorb, various sublingual (SL) has been prepared The tablet containing cyclobenzaprine HCl or amitriptyline HCl of dosage form.However, sublingual and oral preparaton can have There are a stability problem of APIs and physical composition itself, especially there are basifiers (to replace in cyclobenzaprine HCl or Ah meter Increase the compound of pH value of solution after woods HCl dissolution) in the case where.Therefore, increase cyclobenzaprine HCl or amitriptyline HCl The method or composition of the stability of (presence or absence of basifier) in the formulation will be useful.
Brief summary of the invention
Some embodiments of the present invention are:
1. pharmaceutical composition, the eutectic mixture comprising mannitol and cyclobenzaprine HCl.
2. the pharmaceutical composition of embodiment 1 includes 60%-90% cyclobenzaprine HCl and 40%-10% mannitol, presses Poidometer.
3. the pharmaceutical composition of embodiment 2, the amount comprising being selected from following cyclobenzaprine HCl and mannitol: 60% ± 2% cyclobenzaprine HCl and 40% ± 2% mannitol, 65% ± 2% cyclobenzaprine HCl and 35% ± 2% mannitol, 70% ± 2% cyclobenzaprine HCl and 30% ± 2% mannitol, 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, 80% ± 2% cyclobenzaprine HCl and 20% ± 2% mannitol, 85% ± 2% cyclobenzaprine HCl and 15% ± 2% mannitol, and 90% ± 2% cyclobenzaprine HCl and 10% ± 2% mannitol, by weight.
4. the pharmaceutical composition of embodiment 3 includes 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, presses Poidometer.
5. the pharmaceutical composition of any one of embodiment 1-4, wherein cyclobenzaprine HCl: mannitol molar ratio is 1.76 ±0.1。
6. the pharmaceutical composition of any one of embodiment 1-5, wherein cyclobenzaprine HCl is the cyclobenzaprine of micronized HCl。
7. the pharmaceutical composition of any one of embodiment 1-6 also includes basifier.
8. the pharmaceutical composition of embodiment 7, wherein basifier is K2HPO4。
9. the pharmaceutical composition of embodiment 7, wherein basifier is Na2HPO4。
10. the pharmaceutical composition of embodiment 7, wherein basifier is anhydrous citric acid trisodium.
11. the method for preparing the eutectic mixture composition of any one of embodiment 1-10, including mixing ring benzene are pricked Woods HCl and mannitol or grinding cyclobenzaprine HCl and mannitol.
12. the method for embodiment 11, including grinding cyclobenzaprine HCl and mannitol.
13. the method for embodiment 12, wherein cyclobenzaprine HCl and mannitol are ground in high shear granulator.
14. the method for embodiment 11, including mixing cyclobenzaprine HCl and mannitol.
15. the method for embodiment 14, wherein cyclobenzaprine HCl and mannitol are mixed via compression.
16. the method for embodiment 15, wherein cyclobenzaprine HCl and mannitol are compressed via rolling.
17. the method for preparing the eutectic mixture composition of any one of embodiment 1-10, including spray drying ring Benzene pricks woods HCl and mannitol.
18. the method for any one of embodiment 11-17, wherein cyclobenzaprine HCl is the cyclobenzaprine HCl of micronized.
19. the method for any one of embodiment 11-18, wherein described pharmaceutical composition includes basifier.
20. the method for embodiment 19, wherein basifier is K2HPO4。
21. the method for embodiment 19, wherein basifier is Na2HPO4。
22. the method for embodiment 19, wherein basifier is anhydrous citric acid trisodium.
23. pharmaceutical composition, the eutectic mixture comprising mannitol and amitriptyline HCl.
24. the pharmaceutical composition of embodiment 23, wherein the eutectic mixture is melted in 133 ± 3 DEG C.
It include 60%-90% amitriptyline HCl and 40%-10% mannitol 25. the pharmaceutical composition of embodiment 23, By weight.
26. the pharmaceutical composition of embodiment 25, the amount comprising being selected from following amitriptyline HCl and mannitol: 40% ± 2% amitriptyline HCl and 60% ± 2% mannitol, 45% ± 2% amitriptyline HCl and 55% ± 2% mannitol, 50% ± 2% amitriptyline HCl and 50% ± 2% mannitol, 55% ± 2% amitriptyline HCl and 45% ± 2% mannitol, 60% ± 2% amitriptyline HCl and 40% ± 2% mannitol, 65% ± 2% amitriptyline HCl and 35% ± 2% mannitol, 70% ± 2% amitriptyline HCl and 30% ± 2% mannitol, 75% ± 2% amitriptyline HCl and 25% ± 2% mannitol, 80% ± 2% amitriptyline HCl and 20% ± 2% mannitol, 85% ± 2% amitriptyline HCl and 15% ± 2% mannitol, With 90% ± 2% amitriptyline HCl and 10% ± 2% mannitol, by weight.
It include 75% ± 2% amitriptyline HCl and 25% ± 2% mannitol 27. the pharmaceutical composition of embodiment 26, By weight.
It include 50% ± 2% amitriptyline HCl and 50% ± 2% mannitol 28. the pharmaceutical composition of embodiment 26, By weight.
29. the pharmaceutical composition of any one of embodiment 23-28, wherein amitriptyline HCl is that the Ah meter of micronized replaces Woods HCl.
30. the pharmaceutical composition of any one of embodiment 23-29 also includes basifier.
31. the pharmaceutical composition of embodiment 30, wherein basifier is K2HPO4。
32. the pharmaceutical composition of embodiment 30, wherein basifier is Na2HPO4。
33. the pharmaceutical composition of embodiment 30, wherein basifier is anhydrous citric acid trisodium.
34. the pharmaceutical composition of any one of embodiment 1-10 and 23-33, wherein mannitol is β mannitol.
35. the pharmaceutical composition of embodiment 34, wherein the composition includes cyclobenzaprine HCl and the eutectic Mixture is melted in 143.6 ± 3 DEG C.
36. the pharmaceutical composition of any one of embodiment 1-10 and 23-33, wherein mannitol is δ mannitol.
37. the pharmaceutical composition of embodiment 36, wherein the composition includes cyclobenzaprine HCl and the eutectic Mixture is in 134 DEG C of ± 3 DEG C of fusings.
38. the method for preparing the eutectic mixture composition of any one of embodiment 23-35, including mixing Ah meter For woods HCl and mannitol or grinding amitriptyline HCl and mannitol.
39. the method for embodiment 38, including grinding amitriptyline HCl and mannitol.
40. the method for embodiment 39, wherein amitriptyline HCl and mannitol are ground in high shear granulator.
41. the method for embodiment 38, including mixing amitriptyline HCl and mannitol.
42. the method for embodiment 41, wherein amitriptyline HCl and mannitol are mixed via compression.
43. the method for embodiment 42, wherein amitriptyline HCl and mannitol are compressed via rolling.
44. the method for preparing the eutectic mixture composition of any one of embodiment 23-34 and 36, including it is spraying Dry amitriptyline HCl and mannitol.
45. the method for any one of embodiment 38-44, wherein amitriptyline HCl is the amitriptyline HCl of micronized.
46. the method for any one of embodiment 38-45, wherein described pharmaceutical composition includes basifier.
47. the method for embodiment 46, wherein basifier is K2HPO4。
48. the method for embodiment 46, wherein basifier is Na2HPO4。
49. the method for embodiment 46, wherein basifier is anhydrous citric acid trisodium.
50. the method for any one of embodiment 11-22 and 38-49, wherein the eutectic mixture composition includes β mannitol.
51. the method for embodiment 50, wherein the composition include cyclobenzaprine HCl and eutectic mixture in 143.6 ± 3 DEG C of fusings.
52. the method for any one of embodiment 11-22 and 38-49, wherein the eutectic mixture composition includes δ mannitol.
53. the method for embodiment 52, wherein the composition includes cyclobenzaprine HCl and the eutectic mixes Object is in 134 DEG C of ± 3 DEG C of fusings.
Detailed description of the invention
Fig. 1: cyclobenzaprine HCl DSC heating curves.
Fig. 2: the DSC heating curves of cyclobenzaprine HCl+ sodium stearyl fumarate 1:1.
Fig. 3: the DSC heating curves of cyclobenzaprine HCl+ sodium stearyl fumarate, preparaton ratio.
Fig. 4: the DSC heating curves of cyclobenzaprine HCl+ potassium hydrogen phosphate 1:1.
Fig. 5: the DSC heating curves of cyclobenzaprine HCl+ potassium hydrogen phosphate, preparaton ratio.
The DSC heating curves of Fig. 6: cyclobenzaprine HCl+ Crospovidone (Kollidon CL) 1:1.
The DSC heating curves of Fig. 7: cyclobenzaprine HCl+ silicon (colloid) 1:1.
Fig. 8: cyclobenzaprine HCl+PearlitolThe DSC heating curves of 1:1.
Fig. 9: cyclobenzaprine HCl+PearlitolDSC heating curves, preparaton ratio.
The DSC heating curves of Figure 10: cyclobenzaprine HCl+Opadry Clear 1:1.
The DSC heating curves of Figure 11: cyclobenzaprine HCl+Opadry II Clear 1:1.
Figure 12: DSC heating curves finally prepares agent composition relatively.
Figure 13: DSC heating curves, the cyclobenzaprine HCl tablet of relative time zero.
Figure 14: DSC heating curves, the opposite cyclobenzaprine HCl tablet at 40 DEG C.
Figure 15: DSC heating curves, the opposite cyclobenzaprine HCl tablet after 50 DEG C of storages.
Figure 16: cyclobenzaprine HCl DSC heating curves.
Figure 17: cyclobenzaprine HCl+ anhydrous sodium phosphate 1:1 (mixture A) DSC heating curves.
Figure 18: cyclobenzaprine HCl+ anhydrous sodium phosphate 1:1 (mixture B) DSC heating curves.
The comparison of Figure 19: cyclobenzaprine HCl+ anhydrous sodium phosphate 1:1 (mixture A&B) DSC heating curves.
Figure 20: cyclobenzaprine HCl+ sodium phosphate dihydrate 1:1 (mixture A) DSC heating curves.
Figure 21: cyclobenzaprine HCl+ sodium phosphate dihydrate 1:1 (mixture B) DSC heating curves.
The comparison of Figure 22: cyclobenzaprine HCl+ sodium phosphate dihydrate 1:1 (mixture A&B) DSC heating curves.
Figure 23: cyclobenzaprine HCl+ sodium phosphate heptahydrate 1:1 (mixture A) DSC heating curves.
Figure 24: cyclobenzaprine HCl+ sodium phosphate heptahydrate 1:1 (mixture B) DSC heating curves.
The comparison of Figure 25: cyclobenzaprine HCl+ sodium phosphate heptahydrate 1:1 (mixture A&B) DSC heating curves.
Figure 26: cyclobenzaprine HCl+ sodium citrate dihydrate 1:1 (mixture A) DSC heating curves.
Figure 27: cyclobenzaprine HCl+ sodium citrate dihydrate 1:1 (mixture B) DSC heating curves.
The comparison of Figure 28: cyclobenzaprine HCl+ sodium citrate dihydrate 1:1 (mixture A&B) DSC heating curves.
Figure 29: cyclobenzaprine HCl+The DSC of 1:1 (mixture A) heats bent Line.
Figure 30: cyclobenzaprine HCl+The DSC of 1:1 (mixture B) heats bent Line.
Figure 31: cyclobenzaprine HCl+The comparison of the DSC heating curves of 1:1 (mixture A&B).
Figure 32: cyclobenzaprine HCl+ sorbierite 1:1 (mixture A) DSC heating curves.
Figure 33: cyclobenzaprine HCl+ sorbierite 1:1 (mixture B) DSC heating curves.
The comparison of Figure 34: cyclobenzaprine HCl+ sorbierite 1:1 (mixture A&B) DSC heating curves.
Figure 35: cyclobenzaprine HCl+ sorbierite 1:1 (mixture B) overlapping XRPD map.
Figure 36: cyclobenzaprine HCl+ mannitol 1:1 (mixture A) DSC heating curves.
Figure 37: cyclobenzaprine HCl+ mannitol 1:1 (mixture B) DSC heating curves.
The comparison of Figure 38: cyclobenzaprine HCl+ mannitol 1:1 (mixture A&B) DSC heating curves.
Figure 39: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A) DSC heating curves.
Figure 40: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A) DSC heating curves.
The comparison of Figure 41: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A&B) DSC heating curves.
Figure 42: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture A) DSC heating curves.
Figure 43: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture B) DSC heating curves.
The comparison of Figure 44: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture A&B) DSC heating curves.
Figure 45: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A) FT-IR/ATR overlapped spectra.
Figure 46: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A) FT-IR/ATR overlapped spectra.
Figure 47: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A) FT-IR/ATR overlapped spectra.
Figure 48: cyclobenzaprine HCl+ anhydrous citric acid sodium 1:1 (mixture A&B) FT-IR/ATR overlapped spectra.
Figure 49: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture A) FT-IR/ATR overlapped spectra.
Figure 50: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture A) FT-IR/ATR overlapped spectra.
Figure 51: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture A) FT-IR/ATR overlapped spectra.
Figure 52: cyclobenzaprine HCl+ glycine carbonic acid disodium 1:1 (mixture A&B) FT-IR/ATR overlapped spectra.
Figure 53: cyclobenzaprine HCl DSC heating curves.
Figure 54: the DSC heating curves of mannitol beta form.
Figure 55: the mixture of cyclobenzaprine HCl and mannitol in 15% API DSC heating curves.
Figure 56: the mixture of cyclobenzaprine HCl and mannitol in 30% API DSC heating curves.
Figure 57: the mixture of cyclobenzaprine HCl and mannitol in 40% API.44 DSC heating curves.
Figure 58: the mixture of cyclobenzaprine HCl and mannitol in 45% API DSC heating curves.
Figure 59: the mixture of cyclobenzaprine HCl and mannitol in 50% API DSC heating curves.
Figure 60: the mixture of cyclobenzaprine HCl and mannitol in 65% API DSC heating curves.
Figure 61: the mixture of cyclobenzaprine HCl and mannitol in 75% API DSC heating curves.
Figure 62: the mixture of cyclobenzaprine HCl and mannitol in 80% API DSC heating curves.
Figure 63: the mixture of cyclobenzaprine HCl and mannitol in 90% API DSC heating curves.
Figure 64: the mixture of cyclobenzaprine HCl and mannitol in 95% API DSC heating curves.
Figure 65: the phasor of the binary mixture of cyclobenzaprine HCl and mannitol.
Figure 66: figure of the fusion enthalpy as the function of API percentage.
Figure 67: cyclobenzaprine HCl XRPD figure.
Figure 68: the cyclobenzaprine HCl peak XRPD (table).
Figure 69: the XRPD figure of mannitol beta form.
Figure 70: the peak XRPD (table) of mannitol beta form.
Figure 71: the overlapping XRPD map of pure compound and eutectic mixture.
Figure 72: the overlapping XRPD map of pure compound and mixture.
Figure 73: mannitol peak is linear 14.1-15 ° of 2 θ range.
The peak Figure 74: API is linear 12.5-13.3 ° of 2 θ range.
Figure 75: amitriptyline HCl DSC heating curves.
Figure 76: the DSC heating curves of amitriptyline HCl+ sodium stearyl fumarate 1:1.
Figure 77: the DSC heating curves of amitriptyline HCl+ stearic acid 1:1.
Figure 78: the DSC heating curves of amitriptyline HCl+ dibehenolin 1:1.
Figure 79: the DSC heating curves of amitriptyline HCl+ magnesium stearate 1:1.
The DSC heating curves of Figure 80: amitriptyline HCl+Pearlitol Flash 1:1.
The eutectic of the DSC heating curves of Figure 81: API+Pearlitol 1:1 is evaluated.
Figure 82: the DSC heating curves of amitriptyline HCl+Pearlitol 200SD/ mannitol 1:1.
The eutectic of the DSC heating curves of Figure 83: API+Pearlitol/ mannitol 1:1 is evaluated.
The DSC heating curves of the cornstarch 1:1 of Figure 84: amitriptyline HCl+Unipure DW/ part pregelatinated.
The DSC heating curves of Figure 85: amitriptyline HCl+ Crospovidone-Kollidon CL 1:1.
Figure 86: amitriptyline HCl+ colloidal silicon/aerosil 2001:1 DSC heating curves.
Figure 87: the DSC heating curves of amitriptyline HCl+ dibastic sodium phosphate 1:1.
Figure 88: the DSC heating curves of amitriptyline HCl+ sodium bicarbonate 1:1.
Figure 89: the DSC heating curves of amitriptyline HCl+ sodium carbonate 1:1.
Figure 90: the DSC heating curves of amitriptyline HCl+ sodium phosphate dodecahydrate 1:1.
Figure 91: the DSC heating curves of amitriptyline HCl+ anhydrous sodium phosphate 1:1.
Figure 92: pass through the SEM for the particle that wet granulation is formed.
Figure 93: the SEM of pure cyclobenzaprine HCl.
Figure 94: the SEM of pure mannitol.
Figure 95: the particle size distribution of the eutectic mixture of wet granulation.
Figure 96: the pore volume vs diameter of the eutectic mixture of wet granulation.
Figure 97: the DSC heating curves of cyclobenzaprine HCl/ mannitol eutectic mixture.
Figure 98: the XRPD figure of cyclobenzaprine HCl/ mannitol eutectic mixture.
Figure 99: the SEM of the mannitol of spray drying.
Figure 100: the SEM of the mannitol of spray drying.
Figure 101: the DSC heating curves of the mannitol of spray drying.
The DSC heating curves of ± 75% mannitol weight (spray drying) of Figure 102: 25% cyclobenzaprine HCl weight.
The DSC heating curves of ± 50% mannitol weight (spray drying) of Figure 103: 50% cyclobenzaprine HCl weight.
The DSC heating curves of ± 25% mannitol weight (spray drying) of Figure 104: 75% cyclobenzaprine HCl weight.
The DSC heating curves of ± 10% mannitol weight (spray drying) of Figure 105: 90% cyclobenzaprine HCl weight.
The phasor of Figure 106: the cyclobenzaprine HCl eutectic mixture formed after spray drying with δ mannitol.
Figure 107: the XRPD of cyclobenzaprine HCl and the mannitol of spray drying figure.
Figure 108: following overlapping XRPD figure: ± 75% mannitol weight of 25% cyclobenzaprine HCl weight, spray drying； ± 50% mannitol weight of 50% cyclobenzaprine HCl weight, spray drying；± 25% mannitol of 75% cyclobenzaprine HCl weight Weight, spray drying；With ± 10% mannitol weight of 90% cyclobenzaprine HCl weight, spray drying.
Figure 109: the SEM of cyclobenzaprine HCl/ δ mannitol eutectic mixture.
Figure 110: the SEM of cyclobenzaprine HCl/ δ mannitol eutectic mixture.
Figure 111: the particle size distribution of the eutectic mixture of spray drying.
Figure 112: the pore volume vs diameter of the eutectic mixture of spray drying.
+ 75% cyclobenzaprine HCl (spray drying) of Figure 113: 25% mannitol；Scheme with the XRPD of cyclobenzaprine HCl.
+ 75% cyclobenzaprine HCl (spray drying) of Figure 114: 25% mannitol；Scheme with the XRPD of cyclobenzaprine HCl.
+ 75% cyclobenzaprine HCl (spray drying) of Figure 115: 25% mannitol；Cyclobenzaprine HCl；With spray drying The XRPD of mannitol schemes.
+ 75% cyclobenzaprine HCl (spray drying) of Figure 116: 25% mannitol；Cyclobenzaprine HCl；With spray drying The XRPD of mannitol schemes.
Figure 117: cyclobenzaprine HCl ionizes in the theoretical of different pH.
Figure 118: solubility test of (WG) the cyclobenzaprine eutectic mixture of wet granulation in following: 1) sodium acetate And sodium chloride；2) potassium dihydrogen phosphate；3) tetrasodium pyrophosphate and 4) sodium acetate, in pH 4.5, in 60 minutes.
Figure 119: cyclobenzaprine HCl (API)；The cyclobenzaprine HCl/ mannitol eutectic that wet granulation (WG) is formed is mixed Close object；The cyclobenzaprine HCl/ mannitol eutectic mixture that dry mixed (MIX) is formed；It is formed with spray drying (SD) The solubility test of cyclobenzaprine HCl/ mannitol eutectic mixture: in tetrasodium pyrophosphate and methylcellulose, in pH 4.5, in 6 hours.
Figure 120: the detailed description of the solubility test in Figure 119 first 60 minutes.
Detailed description of the invention
Unless otherwise defined herein, scientific and technical terms used herein should have ordinary skill people The meaning that member is commonly understood by.In general, for pharmacology described herein, cell and tissue culture, molecular biology, Cell and cancer biology, Neurobiology, neurochemistry, virology, immunology, microbiology, science of heredity and protein and core Acidification learn used in technology and name be well known in the art and those of generally use.
Unless otherwise specified, methods and techniques of the invention are generally according to well known in the art and be described in various one As and the conventional method of bibliography particularly carry out, the bibliography has reference and discussion throughout this manual.
The technical terms of chemistry used herein use such as " The McGraw-Hill according to this field common usage Dictionary of Chemical Terms",Parker S.,Ed., McGraw-Hill,San Francisco,C.A. (1985)。
The above-mentioned full content referred in the application and any other disclosure, patent and disclosed patent application pass through It quotes and is specifically incorporated herein.The contradiction the case where, it is subject to the present specification including its specific definitions.
This specification in the whole text, wording " including " or variation such as " include " or " covering " be understood to mean that include into The entirety (or component) or one group are whole (or component), but are not excluded for any other entirety (or component) or one group whole Body (or component).
Singular " one ", " one kind " and " one " include plural number, unless expressly specified otherwise.
Term " including ", which is used to refer to, " includes but is not limited to." " includes that " with " includes but is not limited to " to be interchangeably used.
" patient ", " subject " or " individual " are interchangeably used and refer to the mankind or non-human animal.These terms Including the mammal such as mankind, primate, animals (including ox, pig etc.), companion animals (such as dog, cat etc.) and nibble Tooth class (such as mouse and rat).
" treatment " illness or patient, which refer to take, to be obtained beneficial or wishes that result includes the steps that clinical effectiveness.It is beneficial or Desired clinical effectiveness includes but is not limited to the mitigation of one or more symptoms related with disease as described herein or illness Or improve.
" giving " or " administration " substance, compound or reagent to subject can be with well known by persons skilled in the art each One of kind of method carries out.For example, compound or reagent can be sublingual or intranasal, given by sucking lung or rectum.It gives It can also carry out such as 1 time, repeatedly and/or in one or more extended periods carry out.In some aspects, administration includes Being directly administered includes self administration and indirect delivery includes outputing drug prescription.For example, as used herein, doctor instructs patient It itself gives drug, or gives the drug prescription that drug and/or provide to patient gives drug to patient by other people.
In solid pharmaceutical products preparaton, the knowledge of the possibility interaction between drug substance and excipient is Prediction is chemically and physically in place of the key of stability.
Excipient can usually modify the biological activity and chemical stability of API, and reason is dissolution or chemical structure It changes.In some cases, excipient can improve chemical stability feature at any time and avoid final dosage form not Desired physical behavio(u)r.
Eutectic mixture system is the mixture of compound or the element with single chemical component, than the phase Any other composition of congruent composition is lower temperature melting.Composition comprising eutectic mixture is known as eutectic Blend composition and its fusion temperature is known as eutectic temperature.It, should be by dividing in order to define eutectic mixture composition Different Compound ratios are analysed to establish binary phase diagraml.
The effect of tablet properties is shown in eutectic mixture, and compacting, which provides, is sufficient to make eutectic mixture shape At close contact and mutual solubility.Eutectic mixture composition usually has than its off-eutectic mixtures counterpart Higher stability and/or rate of dissolution.Because of eutectic mixture enhancing dissolution, they can be used to increase in solid point Permeability in granular media and dispersion system.However, develop it is certain at tablet form when, it is undesirable to eutectic mixture shape At the undesirable physically or chemically changing features that can result in tablet (during preparation manipulation such as wet granulation), such as The low melting temperature of eutectic mixture, adhesion, uncertain hardness, unstability are difficult to accelerate to evaluate stability.
Mannitol and sorbierite are the excipient being generally used in solid pharmaceutical products.Mannitol and sorbierite are 6- carbon Sugar alcohol isomers.Sugar alcohol is hydrogenated carbohydrate, and carbonyl has been reduced to primary hydroxyl or secondary hydroxyl.Other 6- carbon sugar alcohols Including inositol, galactitol, fucitol and iditol.
It is usually because they provide quality although mannitol and sorbierite can be included in pharmaceutical composition Cooling effect in benefit such as sweet taste or mouth and be physical inertness.To it was unexpectedly determined that discovery mannitol and ring benzene It pricks woods HCl and forms eutectic mixture composition with amitriptyline HCl.By comparison, sorbierite dissolves cyclobenzaprine HCl Eutectic mixture is not formed, this emphasizes the unpredictability that eutectic mixture is formed and is formed with mannitol low total The protectiveness effect of molten mixture.It is without being bound by theory, it is possible to which that two of mannitol and cyclobenzaprine HCl penetrate crystalline substance altogether Lattice provide for cyclobenzaprine HCl to aquation and other chemically interactive protections.
Compound
Compound for embodiment of the present invention includes cyclobenzaprine HCl and amitriptyline HCl.In certain embodiment party In formula, compound is micronized.In alternative embodiment, compound is not micronized.In some embodiments, Compound can reside in one or more crystal isotypes.
As used herein, " cyclobenzaprine HCl " refers to the pharmaceutically acceptable cyclobenzaprine hydrochloride of cyclobenzaprine.
As used herein, " amitriptyline HCl " refers to the pharmaceutically acceptable amitriptyline hydrochloride of amitriptyline.
Eutectic mixture composition
In some embodiments, the present invention provides the eutectic mixture comprising mannitol and active pharmaceutical ingredient Pharmaceutical composition.In some embodiments, active pharmaceutical ingredient is cyclobenzaprine HCl or amitriptyline HCl.
In some embodiments, the present invention provides the medicine of the eutectic mixture comprising mannitol and cyclobenzaprine HCl Compositions.In some embodiments (for example, in the case where composition includes β mannitol eutectic mixture), low total Molten mixture has 143.6 ± 3 DEG C of fusion temperature.In some embodiments, the fusion temperature of eutectic mixture is big About 135.6 DEG C, 136.6 DEG C, 137.6 DEG C, 138.6 DEG C, 139.6 DEG C, 140.6 DEG C, 141.6 DEG C, 142.6 DEG C, 143.6 DEG C, 144.6 DEG C, 145.6 DEG C, 146.6 DEG C, 147.6 DEG C, 148.6 DEG C, 149.6 DEG C, 150.6 DEG C, 151.6 DEG C, 152.6 DEG C, or 153.6℃.In some embodiments (for example, in the case where composition includes δ mannitol eutectic mixture), low total Molten mixture has 134 ± 3 DEG C of fusion temperature.In some embodiments (for example, including that δ mannitol is low total in composition Molten mixture), the fusion temperature of eutectic mixture is about 124 DEG C, 125 DEG C, 126 DEG C, 127 DEG C, 128 DEG C, 129 DEG C, 130 DEG C, 131 DEG C, 132 DEG C, 133 DEG C, 134 DEG C, 135 DEG C, 136 DEG C, 137 DEG C, 138 DEG C, 139 DEG C, 140 DEG C, 141 DEG C, 142 DEG C, 143 DEG C or 144 DEG C.In special embodiment, the fusion temperature of eutectic mixture is the temperature that fusing starts. In alternative embodiment, the fusion temperature of eutectic mixture is to observe the temperature of maximum fusing.In certain embodiments In, composition includes the cyclobenzaprine HCl greater than 5% and the mannitol less than 95%, by weight.In certain embodiments In, composition includes the mannitol of the cyclobenzaprine HCl and 99%-95% of 1%-5%, by weight.In certain embodiments In, composition includes the mannitol of the cyclobenzaprine HCl and 95%-90% of 5%-10%, by weight.In certain embodiment party In formula, composition includes the mannitol of the cyclobenzaprine HCl and 90%-80% of 10%-20%, by weight.In certain realities It applies in mode, composition includes the mannitol of the cyclobenzaprine HCl and 90%-10% of 10%-90%, by weight, such as The mannitol of the cyclobenzaprine HCl and 40%-10% of 60%-90% or the cyclobenzaprine HCl and 30%-20% of 70%-80% Mannitol, by weight.Exemplary composition include 60% ± 2% cyclobenzaprine HCl and 40% ± 2% mannitol, 65% ± 2% cyclobenzaprine HCl and 35% ± 2% mannitol, 70% ± 2% cyclobenzaprine HCl and 30% ± 2% mannitol, 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, 80% ± 2% cyclobenzaprine HCl and 20% ± 2% mannitol, 85% ± 2% cyclobenzaprine HCl and 15% ± 2% mannitol and 90% ± 2% cyclobenzaprine HCl and 10% ± 2% sweet dew Alcohol, by weight.In some embodiments, composition includes 75% ± 10% cyclobenzaprine HCl and 25% ± 10% sweet dew Alcohol, by weight.In some embodiments, composition includes 75% ± 2% cyclobenzaprine HCl and 25% ± 2% sweet dew Alcohol, by weight.In some embodiments, composition includes 75% cyclobenzaprine HCl and 25% mannitol, by weight. In some embodiments, composition includes cyclobenzaprine HCl and mannitol, wherein cyclobenzaprine HCl: mannitol molar ratio It is 1.70 ± 0.1 to 1.80 ± 0.1.In some embodiments, the molar ratio is about 1.6 to 2.0.Particularly implementing In mode, the molar ratio is 1.70 ± 0.1,1.71 ± 0.1,1.72 ± 0.1,1.73 ± 0.1,1.74 ± 0.1,1.75 ± 0.1,1.76 ± 0.1,1.77 ± 0.1,1.78 ± 0.1,1.79 ± 0.1 or 1.80 ± 0.1.In some embodiments, institute State molar ratio be 1.60 ± 0.5,1.65 ± 0.5,1.70 ± 0.5,1.75 ± 0.5,1.80 ± 0.5,1.85 ± 0.5,1.90 ± 0.5,1.95 ± 0.5 or 2.0 ± 0.5.In some embodiments, the molar ratio is 1.76 ± 0.1.In certain embodiment party In formula, the molar ratio is 1.76 ± 0.5.
In some embodiments, the present invention provides pharmaceutical composition, low total comprising mannitol and amitriptyline HCl Molten mixture.In some embodiments, composition has 133 ± 3 DEG C of fusion temperature.In some embodiments, it combines The fusion temperature of object is about 125 DEG C, 126 DEG C, 127 DEG C, and 128 DEG C, 129 DEG C, 130 DEG C, 131 DEG C, 132 DEG C, 133 DEG C, 134 DEG C, 135 DEG C, 136 DEG C, 137 DEG C, 138 DEG C, 139 DEG C, 140 DEG C, 141 DEG C, 142 DEG C or 143 DEG C.In special embodiment In, the fusion temperature of eutectic mixture is the temperature that fusing starts.In alternative embodiment, eutectic mixture melts Changing temperature is to observe the temperature of maximum fusing.In some embodiments, composition include be greater than 5% amitriptyline HCl and Less than 95% mannitol, by weight.In some embodiments, composition include 1%-5% amitriptyline HCl and 99%-95% mannitol, by weight.In some embodiments, composition include 5%-10% amitriptyline HCl and 95%-90% mannitol, by weight.In some embodiments, composition include 10%-20% amitriptyline HCl and 90%-80% mannitol, by weight.In some embodiments, composition include 10%-90% amitriptyline HCl and 90%-10% mannitol, by weight, such as 60%-90% amitriptyline HCl and 40%-10% mannitol or 70%- 80% amitriptyline HCl and 30%-20% mannitol, by weight.Exemplary composition includes 60% ± 2% amitriptyline HCl and 40% ± 2% mannitol, 65% ± 2% amitriptyline HCl and 35% ± 2% mannitol, 70% ± 2% amitriptyline HCl and 30% ± 2% mannitol, 75% ± 2% amitriptyline HCl and 25% ± 2% mannitol, 80% ± 2% amitriptyline HCl and 20% ± 2% mannitol, 85% ± 2% amitriptyline HCl and 15% ± 2% mannitol and 90% ± 2% Ah meter For woods HCl and 10% ± 2% mannitol, by weight.In some embodiments, composition includes 75% ± 10% Ah meter For woods HCl and 25% ± 10% mannitol, by weight.In some embodiments, composition includes 75% ± 2% Ah meter For woods HCl and 25% ± 2% mannitol, by weight.In some embodiments, composition includes 75% amitriptyline HCl With 25% mannitol, by weight.In some embodiments, composition include amitriptyline HCl and mannitol, wherein Ah Rice replaces woods HCl: mannitol molar ratio 1.70 ± 0.1 to 1.80 ± 0.1.In some embodiments, the molar ratio is 1.70 ± 0.1,1.71 ± 0.1,1.72 ± 0.1,1.73 ± 0.1,1.74 ± 0.1,1.75 ± 0.1,1.76 ± 0.1,1.77 ± 0.1, 1.78 ± 0.1,1.79 ± 0.1 or 1.80 ± 0.1.In some embodiments, the molar ratio is 1.76 ± 0.1.
The another benefit of eutectic mixture composition of the present invention is to increase the stability of the tablet of the HCl containing cyclobenzaprine. In some embodiments, the present invention provides pharmaceutical composition, includes cyclobenzaprine HCl and mannitol or amitriptyline HCl And mannitol, wherein with the identical tablet without mannitol for example comprising sorbierite rather than compared with the tablet of mannitol, piece dosage form The composition of formula has increased stability.In fact, containing cyclobenzaprine HCl, K2HPO4Tablet with mannitol is at 40 DEG C Stablize 3 months with 75% relative humidity.By comparison, contain cyclobenzaprine HCl, K in the same terms storage2HPO4And sorb The tablet of alcohol is reaching just disintegration even before 1 week.
In some embodiments, the present invention provide comprising cyclobenzaprine HCl and mannitol or amitriptyline HCl and The pharmaceutical composition of mannitol, wherein with individually or in the preparaton containing one or more not excipient of basifier In cyclobenzaprine HCl or amitriptyline HCl compare, the composition have stable tablet increased rate of dissolution.Example Such as, in the case where mixing with the 50mM citrate (pH 4) of 100mL for 37.0 ± 0.5 DEG C, composition can be opened up in 5 minutes Show and be greater than 55%, be greater than 50%, be greater than 45%, be greater than 40%, be greater than 35%, is greater than 30%, or the dissolution greater than 25%.Example Such as, in the case where mixing with the 50mM citrate (pH 4) of 100mL for 37.0 ± 0.5 DEG C, composition can be opened up in 10 minutes Show and be greater than 80%, be greater than 75%, be greater than 65%, be greater than 60%, is greater than 55%, the dissolution greater than 50%.For example, 37.0 ± In the case that 0.5 DEG C mixes with the 50mM citrate (pH 4) of 100mL, composition can be shown in 240 minutes to be greater than 80%, it is greater than 75%, is greater than 65%, be greater than 60%, is greater than 55%, the dissolution greater than 50%.
Mannitol can be with 3 kinds of polymorphous state crystallizations: α, β and δ.The characteristics of this 3 kinds of forms can be X-ray powder Last diffraction, and each polymorph has different fusing points.See, for example, Sharma and Kalonia, AAPS PharmaSciTech 5(1):E10(2004).First than observing cyclobenzaprine HCl and mannitol (beta polymorphic form) is low Eutectic mixture is even more surprisingly observed low from the second of different polymorphic forms mannitol (δ polymorph) Eutectic mixture.Eutectic mixture (herein also referred to as " δ comprising δ mannitol and cyclobenzaprine HCl or amitriptyline HCl Mannitol eutectic mixture ") with respect to the eutectic mixture comprising β mannitol and cyclobenzaprine HCl or amitriptyline HCl (herein also referred to as " β mannitol eutectic mixture ") has several advantages.It is especially lower than β mannitol total in them The molten lower fusing point of mixture and the opposite increased dissolution of β mannitol eutectic mixture.
In some embodiments, the present invention is provided comprising cyclobenzaprine HCl and mannitol or amitriptyline HCl and sweet Reveal the eutectic mixture pharmaceutical composition of alcohol, wherein mannitol is in its beta-polymorph form.In some embodiments, this hair It is bright that the eutectic mixture pharmaceutical composition comprising cyclobenzaprine HCl and mannitol or amitriptyline HCl and mannitol is provided, Wherein mannitol is in its δ polymorphic forms.In some embodiments, the pharmaceutical composition comprising beta-polymorph form mannitol Object is sublingual composition.In some embodiments, the pharmaceutical composition comprising beta-polymorph form mannitol is Oral compositions Object.In some embodiments, the pharmaceutical composition comprising δ polymorphic forms mannitol is sublingual composition.In certain implementations In mode, the pharmaceutical composition comprising δ polymorphic forms mannitol is Orally administered composition.It is Orally administered composition in composition In special embodiment, Orally administered composition bioequivalence is in 5mg cyclobenzaprine HCl oral tablet (such as not carrying out riel 5mg). In the special embodiment that composition is Orally administered composition, Orally administered composition bioequivalence is oral in 10mg cyclobenzaprine HCl Tablet (such as not carrying out riel 10mg).Not carry out riel tablet by hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, iron oxygen Compound, lactose, magnesium stearate, starch and titanium dioxide are constituted.10mg t.i.d. is administered in general health volunteer's middle dosage In the case where, stable state AUC (after dosing 4 days) is 177ng.hr/mL (range 80-319 ng.hr/mL) and Cmax It is 25.9ng/mL (range 12.8-46.1ng/mL).The additional pharmacokinetic properties of orally administration cyclobenzaprine can join See such as Winchell et al., J Clin Pharmacol.42 (1): 61-9 (2002) and Hucker et al., J Clin Pharmacol. 17(11-12):719-27(1977)。
In some embodiments, the present invention provides the group of the eutectic mixture comprising mannitol and cyclobenzaprine HCl Close object.In some embodiments, the present invention provides the combination of the eutectic mixture comprising mannitol and amitriptyline HCl Object.It will be appreciated by those skilled in the art that these compositions may be adapted in various ways than as described herein those be administered. For example, composition may be adapted to oral administration (administration, wherein cyclobenzaprine or amitriptyline absorb in the gastrointestinal tract), or warp Mucosa absorption (such as sublingual, cheek or Nasal absorption, or pass through sucking).
The method for preparing eutectic mixture composition
It will be appreciated by those skilled in the art that eutectic mixture composition of the present invention can be according in many known methods It is any to prepare.In some embodiments, the present invention provides the method for generating eutectic mixture composition of the present invention, Including grinding API (cyclobenzaprine HCl or amitriptyline HCl) and mannitol, API (cyclobenzaprine HCl or amitriptyline are mixed HCl) and mannitol, or combinations thereof.For example, API and mannitol can be ground in the agate mortar or in high shear granulator Middle mixing.High shear mixing quick runner and chopping blade mix each ingredient uniformly to merge dried powder.Certain particle rulers It is very little reduction be it is possible, reason is the high speed of shearing force and hybrid blade.API and mannitol also can beIt grinds and mixes in shaking machine-blender.In some embodiments, API and mannitol can be via pressures Contracting is for example mixed via rolling.It rolls between the roll for forcing fine powder to enter two phase reverse rotations and is by material extruding Dense solid or piece (referred to as thin slice).The size of thin slice is reduced until they reach desired particle size.In certain implementations In mode, mannitol can be melted and be mixed to form eutectic mixture with cyclobenzaprine HCl or amitriptyline HCl and combined Object.In some embodiments, API is that (such as the cyclobenzaprine HCl of micronized or the Ah meter of micronized replace by the API of micronized Woods HCl).
In some embodiments, the present invention provides the method for generating eutectic mixture composition of the present invention, including spray The solution of mist dry API (cyclobenzaprine HCl or amitriptyline HCl) and mannitol.It will be appreciated by those skilled in the art that spraying dry Dry is convention, and the parameter of spray drying is determining excessive experiment can be not added.For example, spray drying can be in following conditions In arbitrarily lower carry out:
T entrance (DEG C): 120
T exports (DEG C): 73-76
Feed rate (ml/min): 4
Flow velocity (L/h): 600
It sucks (100%): 100
δ pressure (millibar): 2-10
These conditions can also expand scale to provide more high-throughput preparation.
The method for detecting eutectic mixture composition
The method for detecting eutectic mixture composition is well known.It will be appreciated by those skilled in the art that eutectic mixes Compositions can pass through arbitrarily detecting in these methods.For example, quickly differential scanning calorimetry (" DSC ") can be used To detect eutectic fusing point: evaluating from the heat of eutectic mixture fusing record and by itself and eutectic mixture composition Fusing heat compare.During DSC is slowly scanned, the formation of increased temperature promotion eutectic mixture in crucible, or even Two kinds of components (such as mannitol and cyclobenzaprine HCl) also can be before experiment starts and in the case where unmixed as This.In contrast, quick DSC scanning reduces the time that eutectic mixture composition can be formed in crucible, and reason is Temperature in crucible quicklys increase during analysis and is rapidly achieved the value of mannitol fusing.Another process useful is measurement Compaction force vs.DSC eutectic fusing point.In the method, mixture is prepared with known ratio, is then subjected to sufficiently define Compaction force.Then dsc analysis is carried out, the hot vs power of eutectic mixture fusing is then recorded, and is mapped.By these values with Compared with those of eutectic mixture ratio acquisition, the percentage of eutectic mixture in the formulation is provided.
Can be used to detect the additional method of the amount of eutectic mixture in the composition is to compare tensile strength and compression Power.In the method, tablet only uses mannitol and API to prepare, and uses different compressing forces.For each tablet of preparation, correction The tensile strength of the percentage vs tablet of the eutectic mixture of formation.Exist between tensile strength and intimate contact area Proportional linear correlation.The relevant slope provides the percentage for the eutectic mixture to be formed.
There are lines between the porosity of powder in the percentage and composition of eutectic mixture composition in the formulation Property it is related.In the method, standard curve can generate as follows: sample be prepared with the component of different ratios, wherein in component At least one has a variety of different particle sizes, measures the porosity of specific surface area and powder, and by porosity to low total Molten mixture plotted as percentage.Because there is linear correlation between two parameters, the relevant slope is by mixing eutectic The record of object provides the percentage of the eutectic mixture formed.
Rate of dissolution can also be used to the percentage of detection eutectic mixture, and reason is that eutectic mixture can be with With higher solubility and higher bioavilability.In the method, calculate one-component inherent rate of dissolution ( Disc type specimen holder is used in medium defined and appropriate), then calculate the rate of dissolution of eutectic mixture.Based on thermodynamics Parameter (entropy), eutectic mixture should have rate of dissolution more faster than other mixtures.It is analyzed by these, it is also possible to obtain Obtain the information in relation to tablet efficiency in terms of bioavilability.The approach can also evaluate eutectic mixture vs independent component Mixture more high bioavilability.
Scanning electron microscope (SEM) can be used to the scanning EM of each pure component, eutectic mixture and mixture, and By pointing out that differently shaped particle observes different crystal habits.
The method for giving eutectic mixture composition
The proper method for giving the drug present composition to subject will depend on such as subject age, subject It is active or inactive between when giving, subject when giving between whether undergo the symptom of disease or condition, the degree of symptom, With the chemistry and biology characteristic (such as solubility, digestibility, bioavilability, stability and toxicity) of API.Certain In embodiment, pharmaceutical composition is given for the absorption of oral or transmucosal.
The method that composition is given for oral absorption is well known in the art.For example, composition can by tablet, Capsule, pill or powder are oral to be given.In these embodiments, composition is absorbed after swallowing by gastrointestinal tract.At certain In a little embodiments, composition lacks film or film (such as semipermeable membrane).
It is well known in the art for giving the method that composition is absorbed for transmucosal.It is used for for example, composition can be given Cheek absorption is carried out with spray solution by buccal tablets agent, lozenge, cheek powder and cheek.Composition can be given for passing through Sublingual tablets, sublingual film, liquid, sublingual powder and sublingual spraying solution carry out sublingual absorption.In some embodiments, Composition lacks film or film (such as semipermeable membrane).Composition can be given for intranasally being inhaled by nasal spray It receives.Composition can be given for carrying out lung absorption by atomizable composition and inhalable dried powder.Because of mannitol Powder be U.S. sucking product (trade name:Pharmaxis Ltd.), inhalant can be particularly advantageous Form of medication.When giving via spray or atomizable composition, composition can be prepared as solution with salt water, using benzene Methanol or other suitable preservatives, or the sorbefacient including enhancing bioavilability, fluorocarbon and/or other Solvation or dispersing agent.
Dosage and dosage regimen can by those skilled in the art according to the needs of subject to be treated come really It is fixed.The admissible factor of those skilled in the art is age or the weight of such as subject, disease or illness to be treated The response of seriousness and subject to treatment.The present composition can for example be given on demand or daily.In certain embodiment party In formula, composition can a few hours be given immediately or before sleep before sleep.Administration can be beneficial before sleep , reason is that it provides therapeutic effect before the disease for the treatment of or the symptom of illness start.Dosage administration can occur In transformation period interval.For example, dosage regimen can be for 1 week, and 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 Week, 10 weeks, 11 weeks, 12 weeks or longer.In some embodiments, dosage regimen will continue 1 month, and 2 months, 3 Month, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.
Therapeutical uses
Pharmaceutical composition of the present invention can be used for treating or preventing the development that fibromyalgia syndrome is also referred to as fibrositis (see, e.g., Moldofsky et al., (2011) .J Rheumatol 38 (12): 2653-2663 and Thomas, J Rheumatol 38(12):2499-2500 (2011)).Fibromyalgia is chronic non-inflammatory rheumatism.The American College of Rheumatology (ACR) nineteen ninety disclose fibromyalgia grade scale (Wolfe, F., et al., Arthritis and Rheumatism 33:160-172(1990)).Modification subsequently, for ACR standard is disclosed (Wolfe et al.,J Rheumatol 38(6):1113-22(2011)).The world diagnostic criteria Ye Bei working group network is public It opens, referred to as " Outcome Measures in Rheumatology " clinical test or OMERACT (Mease P, et al.J Rheumatol. 2009；36(10):2318-29.).Fibromyalgia is traditionally characterized as stiff or diffusivity pain, pain, flesh Bitterly, dyssomnias or fatigue.Pain is usually extensive and is generally concentrated at specific " tender spots ", when touched may be used To bring extensive pain and muscle cramp.Other symptoms include spirit and emotional maladjustment is such as absent minded and irritability, Neuropsychic symptom such as depression and anxiety, arthroncus, headache are numb.Fibromyalgia and the sleep for not making mental restoration, Tired, sleepiness, reflux, clouding of consciousness be damaged with cognition includes that multitasking difficulty is related.Fibromyalgia also usually with sleep Dormancy obstacle, fatigue, non-restorative sleep, Mixed anxiety and depressive.The compositions and methods of the invention can be used to treat above-mentioned Any one of illness and any combination thereof.
Fibromyalgia is further classified two classes-primary fibromyalgia or secondary-with fibromyalgia by some practitioners. Generally, primary fibromyalgia syndrome can be considered as there is no the fibromyalgia occurred when another significant illness, and secondary- The fibromyalgia occurred when there are another significant medical disorder can be considered as with fibromyalgia, the medical disorder can be with It is as caused by patient's fibromyalgia or only associated.Secondary or adjoint fibromyalgia can include the fiber in patient Myalgia, with classical or clear rheumatoid arthritis, knee or Hand osteoarthritis, pain in the loins syndrome, cervical syndrome, cancer Pain syndrome, temporomandibular joint disorder, migraine, menopause, posttraumatic stress disorder and interstitial cystitis or painful bladder are comprehensive Levy (or combinations thereof).
The present composition can be used for treat or prevent traumatic event after PTSD symptom development (starting, Consolidation or permanence).Traumatic event is defined as direct personal experience, involves true or menace death or serious wound Evil, or other threats to individual integrality, or see and involve event that is dead, injuring or threaten other people physical integrities；Or Know the death threats of unexpected or violence death, grievous injury or kinsfolk or other person's experience in close relations Or injury.The traumatic event being directly submitted to includes but is not limited to military fistfight, and (property attacks violence personal attack, physics is invaded Attack, plunder, seize), it is kidnaped, is held as a hostage as hostage, terrorist's invasion are tormented, it takes into custody for war or concentration camp prisoner, Natural or human-made disasters, serious motor-vehicle accident, or diagnosis suffer from the disease of life-threatening.For children, sexual trauma sexual behavior part can With include develop unsuitable sex experience and without threatening or true violence or injury.The event seen includes but is not limited to see It examines other people grievous injuries or unnatural death due to insurgent violence, accident, war or disaster or unexpectedly sees corpse Body or body part.The event for knowing that other people undergo can include but is not limited to violence personal attack, major accident or family The grievous injury of member or best of friends experience knows the unexpected unexpected death of kinsfolk or best of friends, or Know the disease that child suffers from life threat.If stressor is mankind's reason (such as torments or rape), obstacle be can be It is especially severe or long-term lasting.The initiation of PTSD symptom generally occurs after traumatic event immediately, during this period PTSD Symptom occurs and becomes increasingly serious.It is there is a kind of " study " or strengthened about a kind of PTSD theory how to develop Journey, traumatic memory is deep-rooted in brains during this period.Since these memories become more constant (the referred to as process of consolidation), Symptom such as flashes back to be increased with the seriousness of bad dream and frequency.Intervention during the material time can prevent some patients Develop fully developed PTSD.The consolidation of PTSD symptom occurs during several weeks and several months generally after traumatic event.People is closed Becoming consolidation in the memory of event is that height is lively and firm memory, with increased frequency again experience such as flash back or Bad dream.During this time period, hyperarousal symptom and avlidance behavior can become increasingly serious and make one impotentia.Once wound The permanence of PTSD symptom then occurs for wound property memory consolidation, and the symptom (flash back and bad dream) and hyperarousal undergone again Symptom becomes to continue and keeps functionally making the unable level of patient.
The present composition can be used to the PTSD hair of the various time interval treatment different phases after traumatic event Exhibition.For example, the initial stage for the treatment of PTSD can need the Quick medicine present composition after traumatic event, such as In first week, in second week, within third week, or in 4th week or later.By comparison, in the reality for the treatment of PTSD When the change stage, those skilled in the art can be later after traumatic event and later during symptom development give this Inventive composition, such as in first month, in second month, or in third month or later.The permanence rank of PTSD Section can be treated with the present composition, after traumatic event 3 months or it is longer give, such as in third month, In four month, in five month or later.As initial, consolidation or permanence phase treatment as a result, PTSD symptom will It is enhanced or eliminates.
The present composition can also be used to treatment traumatic brain injury (TBI).TBI and sleep disturbance, dyssomnias, Fatigue, non-restorative sleep, anxiety are related with depression.The compositions and methods of the invention can also be used to treat above-mentioned illness Any one of, it is combined with treatment TBI or independently for the treatment of TBI.
The present composition also can be used in chronic trauma encephalopathy (CTE).CTE and sleep disturbance, dyssomnias are tired Labor, non-restorative sleep, anxiety are related with depression.The compositions and methods of the invention can also be used to treat in above-mentioned illness It is any, with treatment CTE combine or independently of treat CTE.
The compositions and methods of the invention can be used to treat sleep disturbance or dyssomnias." sleep disturbance " can be Any one of dysfunctional of four kinds of primary categories (DSM-IV, pp. 551-607；Referring also to The International Classification of Sleep Disorders: (ICSD)Diagnostic and Coding Manual,1990,American Sleep Disorders Association).The primary sleep disturbance of one classification includes The not sleep disturbance as caused by another phrenoblabia, substance or general medicine illness.They include but not limited to primary insomnia Disease, primary hypersomnia, narcolepsy, circadian rhythm sleep disturbance, nightmare obstacle, night terror, sleep-walking obstacle, REM Disturbance in sleep behavior, sleep paralysis, day night reversion and other related obstacles；The sleep disturbance that substance induces；With general doctor Learn sleep disturbance caused by illness.Primary insomnia non-restorative sleep is described as the class of primary insomnia by DSM-IV-TR Type, wherein main problem is that despondent or spiritual unrecovered awakening is felt.Second category include be attributable to substance, Including those of drug and drug abuse sleep disturbance.Third classification includes general medicine illness to sleep/awakening system Dyssomnias caused by acting on.The sleep disturbance of 4th classification includes appraisable phrenoblabia such as mood or anxiety disorder Those of cause.The sleep disturbance of 5th classification includes to be described as those of non-restorative sleep.It is non-recovery in DSM-IV-TR Property sleep a definition be primary insomnia type (A1.3), wherein main problem is despondent or spiritual does not restore Awakening feel.The symptom of sleep disturbance of all categories is known in the art." sleep disordered " can be mental restoration and sleep The disease damage of dormancy.Fatigue when above-mentioned clinical diagnosis can describe awake based on patient itself is felt or patient reports inferior sleep Quality carries out.The obstruction of the well sleep quality can be described as shallowly sleeping or frequently awakening, and can replace with the period Mode (CAP) A2 or A3 rate or cycle duration or standardized CAP A2+A3 increase, which depends on non-REM and sleep The CAP (A2+A3) of dormancy/CAP (A1+A2+A3) (see, for example, Moldofsky et al., J Rheumatol 38 (12): 2653- 2663 (2011) and Thomas, (2011) J Rheumatol 38 (12): 2499-2500), the alpha rhythm in non-REM sleep is dirty Dye, or to lack δ wave related during the sleep of deeper physical recovery." dyssomnias " may or may not rise to As defined in DSM-IV " sleep disturbance " is horizontal, but they can share one or more common symptoms.Sleep is lost The symptom of tune is known in the art.It include dazed and confused sense in cardinal symptom, it is tired, feel weak and during recovery time It focuses on difficulty.The sleep correlation illness especially sleep disturbance (example that can be treated with the method for the present invention and composition Such as, inherent sleep disturbance such as subjective sensation is had a sleepless night, Psychophysiological insomnia disease, spontaneous insomnia, obstructive sleep respiratory Suspend syndrome, central sleep apnea, central alveolar hypoventilation syndrome, restless leg syndrome, and week Phase property limb movement disturbance；External sleep disturbance such as Environmental sleep disorder adjusts sleep disturbance, is limited sleep disturbance, excited Agent-dependence sleep disturbance, alcohol dependence sleep disturbance, the sleep disturbance of toxin-induced are urged in relation to the obstacle that sleep starts Dormancy medicine dependence sleep disturbance, unsuitable Sleep hygiene, plateau insomnia, deficiency sleep syndrome, nighteating syndrome, It drinks syndrome with night；With circadian rhythm sleep disturbance such as jet lag, delay sleep phase syndrome, advanced stage sleeps Dormancy phase syndrome, change shifts sleep disturbance, non-24 hours sleep arousal disorders and irregular sleep wakefulness mode), deep dormancy shape State (such as Arousal Disorder such as sleep-walking, confusion are aroused, and the terrified and sleep wakefulness transition obstacle such as rhythm and pace of moving things of sleeping Property dyskinesia, somniloquy and sleep starts and night leg spasm), and it is related with medicine or psychiatric disorders or obstacle Sleep disturbance.The present composition can also be used to treatment muscle cramp.Muscle cramp can have with courbature such as backache It closes.The compositions and methods of the invention can also be used to treat any one of above-mentioned illness, with treatment muscle cramp combine or Independently for the treatment of muscle cramp.
Basifier
The present composition may include basifier.As used herein, " basifier " refers to that raising contains cyclobenzaprine The reagent of the pH of the solution of HCl or amitriptyline HCl is (for example, increase the liquid comprising cyclobenzaprine HCl or amitriptyline HCl The substance of local pH, including potassium dihydrogen phosphate (monopotassium phosphate, an alkali formula potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (di(2-ethylhexyl)phosphate Potassium, two alkali formula potassium phosphates, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (monosodium phosphate, an alkali sodium acid phosphate, NaH2PO4), disodium hydrogen phosphate (disodium hydrogen phosphate, two alkali sodium acid phosphates, Na2HPO4), tertiary sodium phosphate (Na3PO4), anhydrous citric acid Trisodium, bicarbonate or carbonate, borate, hydroxide, silicate, nitrate, the ammonia of dissolution, certain organic acids are total to Yoke alkali (including bicarbonate) and sulfide).Without being bound by theory, basifier is provided beneficial to pharmacokinetics, is attributed to Pharmaceutical composition comprising cyclobenzaprine HCl or amitriptyline HCl, but it can also be due between HCl and basifier Interaction keeps cyclobenzaprine HCl or amitriptyline HCl unstable.To eutectic mixture composition as described herein It can be particularly useful for the composition comprising basifier.
Excipient
In some embodiments, the present composition can be used as drug.In some embodiments, the present invention provides The purposes of the present composition in medicine preparation.In some embodiments, it can valuably wrap in the compositions of the present invention Include one or more excipient.It will be understood by those skilled in the art that selecting any excipient that can influence any other figuration The selection of agent.For example, selecting special excipient that can prevent using one or more additional excipient, reason is to assign The group credit union of shape agent generates undesired effect.Those skilled in the art's meeting can be empirically determined by which kind of additional figuration Agent (if necessary) is included in preparaton of the present invention.For example, cyclobenzaprine HCl or amitriptyline HCl can be at least one Pharmaceutically acceptable carrier is combined, such as solvent, filler, adhesive, moisturizer, disintegrating agent, resistance solvent, disintegrating agent, Glidant, absorbsion accelerator, wetting agent, solubilizer, lubricant, sweetener or corrigent." pharmaceutically acceptable carrier " Refer to compatible with the other ingredients of preparaton and harmless to recipient any diluent or excipient.Pharmaceutically acceptable load Body can be selected based on desired administration route according to standard pharmaceutical practice.
Filler
It in some embodiments, can valuably in the compositions of the present invention include filler.Filler is generally used for In pharmaceutical composition, to provide the adduction volume of composition.Filler is well known in the art.Correspondingly, described herein to fill out Agent is filled it is not expected that constituting exclusive list, but the demonstration that can be used in the compositions and methods of the invention is only provided and is filled out Fill agent.
Exemplary fillers may include carbohydrate, sugar alcohol, amino acid and saccharic acid.Filler includes but is not limited to A kind of, two or more carbohydrate, starch, aldose, ketose, aminosugars, glyceraldehyde, arabinose, lyxose, penta Sugar, ribose, xylose, galactolipin, glucose, hexose, idose, mannose, talose, heptose, glucose, fructose, methyl a- D- glucopyranoside, maltose, lactone, sorbose, erythrose, threose, arabinose, allose, altrose, Gu Luo Sugar, idose, talose, Erythrulose, ribulose, xylulose, psicose, Tagatose, Glucosamine, galactosamine, Araban, levulan, fucan, galactan, polygalacturonic acid, glucan, mannosan, xylan, Synanthrin, levan, fucose, carrageenan, galactolipin Kano sugar (galactocarolose), pectin, amylose, Pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan, chitin, agarose, keratin are soft Ossein, dermatan, hyaluronic acid, xanthine glue, sucrose, trehalose, dextran, lactose, alditol, inositol, sorbierite, Mannitol, glycine, glycuronic acid, uronic acid, aldaric acid, gluconic acid, ISOASCORBIC ACID, vitamin C, glucosaccharic acid, Portugal Grape uronic acid, gluconic acid, glucosaccharic acid, galacturonic acid, mannuronic acid, neuraminic acid, pectic acid, cornstarch, and Alginic acid.
Disintegrating agent
It in some embodiments, can valuably in the compositions of the present invention include disintegrating agent.Disintegrating agent promotes solid The rupture of composition, so that convenient for delivering active pharmaceutical compositions.Disintegrating agent is well known in the art.Some disintegrating agents by Referred to as super-disintegrant, reason is that they have rapid charater, and can be used as disintegrating agent in the context of the present invention. Correspondingly, disintegrating agent described herein is it is not expected that constitute exclusive list, but only provide and can be used for composition of the invention With the exemplary disintegrating agent in method.Exemplary disintegrating agent includes Crospovidone, microcrystalline cellulose, sodium carboxymethylcellulose, Methylcellulose, sodium starch glycolate, carboxymethyl cross-linked carboxymethyl cellulose sodium calcium, polyvinylpyrrolidone, low alkyl group- Substituted hydroxy propyl cellulose, Indion 414, starch, pregelatinized starch, calcium carbonate, natural gum, mosanom and PearlitolPearlitol (Roquette) it is mannitol-cornstarch disintegrating agent, especially sets Meter is used for oral dispersible tablets (ODT).Certain disintegrating agents have effervesce quality.
Glidant
It in some embodiments, can valuably in the compositions of the present invention include glidant.Glidant promotes powder The ability of free-flowing.Glidant is well known in the art.Correspondingly, glidant described herein is it is not expected that constitute exhaustion List, but the exemplary glidant that can be used in the compositions and methods of the invention is only provided.Exemplary glidant includes Colloidal silicon dioxide (silica), magnesium stearate, starch, talcum, Gan You behenic acid ester, DL-leucine, lauryl sulfate Sodium, calcium stearate and odium stearate.
Lubricant
It in some embodiments, can valuably in the compositions of the present invention include lubricant.Lubricant assists in keeping Composition component is from agglomeration.Lubricant is well known in the art.Correspondingly, lubricant described herein is it is not expected that constitute Exclusive list, but the exemplary lubricant that can be used in the compositions and methods of the invention is only provided.Exemplary lubricant Including calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, plant base fatty acid, talcum, mineral oil, light mineral Oil, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, safflower oil, canola Oil, coconut oil and soybean oil), silica, zinc stearate, ethyl oleate, ethyl laurate.
Sweetener
It in some embodiments, can valuably in the compositions of the present invention include sweetener.Sweetener is by group It closes object and assigns the palatability that sweet taste helps improve composition.Sweetener is well known in the art.Correspondingly, sweet tea described herein Taste agent is it is not expected that constitute exclusive list, but only provide the exemplary sweet tea that can be used in the compositions and methods of the invention Taste agent.Exemplary sweetener includes but not limited to selected from following compounds: carbohydrate such as monosaccharide, disaccharides, trisaccharide, polysaccharide and Oligosaccharide；Carbohydrate such as sucrose, glucose (corn syrup), glucose, inverted sugar, fructose, maltodextrin and dextrosan； Saccharin and its salt such as sodium and calcium salt；Cyclamic acid and its salt；Dipeptide sweetener；Chlorination sugar derivatives such as sucralose And dihydrochalcone；Sugar alcohol such as sorbierite, sorbitol syrups, mannitol, xylitol, six-resorcinols etc., and combinations thereof. Potassium, the calcium of hydrogenated starch hydrolysates and 3,6- dihydro-6- methyl-1-1,2,3- oxa-thiazine-4- ketone-2,2- dioxide Also there is use with sodium salt more.
Fragrance
It in some embodiments, can valuably in the compositions of the present invention include fragrance.Fragrance is by composition Assign the palatability that desired taste helps improve composition.Fragrance is well known in the art.Correspondingly, perfume (or spice) described herein Material is it is not expected that constitute exclusive list, but only provide the exemplary fragrance that can be used in the compositions and methods of the invention. Including but not limited to natural and/or synthesis (i.e. artificial) the compound such as peppermint of exemplary fragrance, peppermint, spearmint, Checkerberry, menthol, fennel, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pears, rasp berry, lemon, grape fruit, Orange, Lee, apple, lime, mixed fruit, passion fruit, pomegranate, chocolate (such as white chocolate, milk chocolate, black chalk Power), vanilla, caramel, coffee, fibert, cortex cinnamomi, a combination thereof etc..
Colorant
Colorant can be used to color coded combination object, such as point out the type and dosage of therapeutic agent.Colorant is ability Known to domain.Correspondingly, colorant described herein is it is not expected that constitute exclusive list, but only provide and can be used for this hair Exemplary colorant in bright composition and method.Exemplary colorant includes but is not limited to natural and/or artificial compound Such as FD&C colorant, natural juice concentrate, pigment such as titanium oxide, silica and zinc oxide, a combination thereof etc..
Conjoint therapy
As described above, the present composition and method can be used to treat PTSD, depression, fibromyalgia, traumatic cerebral Damage, sleep disturbance, non-restorative sleep, chronic pain and anxiety disorder.It is any in described treatment method can also be with It is combined with the psychotherapy intervention for improving treatment results.The purpose of exemplary psychotherapy intervention is to modify traumatic Remember or reduce the emotional reactions to traumatic memory, including psychological counseling, cognitive behavioral therapy and eye movement desensitization and Chong Chu Reason, systematic desensitization, relaxation training, biofeedback, cognition processing therapy stress inculcate training, and steadfastness training exposes treatment, Combination stress inculcate trained and exposure treatment, the exposure treatment of combination and relaxation training and recognizing factor.In every case, Intervene purpose and involves the emotional reactions modifying traumatic memory or reducing to traumatic memory.Expected result is usually PTSD disease The improvement of shape or the generation for reducing symptom, the Symptoms are in terms of physiologic response, anxiety, depression and estrangement.
In some embodiments of the present invention, composition is combined with drug, and the drug can further mitigate PTSD symptom, depression, fibromyalgia, traumatic brain injury, sleep disturbance, non-restorative sleep, chronic pain or anxiety disorder. Drug includes α -1- adrenergic aceptor antagonist, beta-adrenergic antagonist, anticonvulsive drug, selective 5- hydroxyl color Amine reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor and antalgesic.Exemplary anticonvulsive drug includes Carbamazepine, Gabapentin, Lamotrigine, Oxcarbazepine, pregabalin, Tiagabine, Topiramate and valproate.It is exemplary α -1- adrenergic aceptor antagonist is prazosin.Exemplary selective serotonin reuptake inhibitor or 5- hydroxyl color Amine-norepinephrine reuptake inhibitor includes Bupropion, Citalopram, desmethylvenlafaxine (desvenlafaxine), Duloxetine, escitalopram, Prozac, escitalopram, Fluvoxamine, Milnacipran, Paro west Spit of fland, Sertraline, Trazodone and Venlafaxine.Exemplary antalgesic includes pregabalin, Gabapentin, paracetamol, C16H25NO2 and non-steroidal anti-inflammatory drugs (for example, brufen and naproxen sodium).It can be applied in combination with the present composition Extra drug includes sodium hydroxybutyrate, zolpidem, Pramipexole, modafinil, Temazepam, Zaleplon and l-modafinil (armodafinil)。
It should be understood that the embodiments of the present invention described are only the examples of certain applications of the principle of the invention.Based on this The introduction of text, those skilled in the art can carry out many modifications without departing from true spirit and range of the invention.
Following embodiments are provided to represent the present invention.These embodiments are not construed as the limitation scope of the invention, and reason exists In these and other comparable embodiment be apparent after referring to disclosure herein, attached drawing and appended claims.
Embodiment
Embodiment 1
The compatibility of the drug products (tablet) containing cyclobenzaprine HCl (API) is evaluated with thermoanalysis technology.It is compatible Property evaluation carried out between the API and many possible excipient of 1:1 ratio.Based on to each component and to the heat of mixture record Event, analysis carry out as follows: the peak that research differential scanning calorimetry (DSC) records in the mixture of API and excipient.It comments Valence is obtained about the difference of the heating curve between mixture after single compound and in the agate mortar abrasive product. After 40 DEG C and 50 DEG C continue 1 month pressure condition, the stability and compatibility of final drug products are also evaluated.
Using following raw materials:
Cyclobenzaprine HCl
Sodium stearyl fumarate
Potassium hydrogen phosphate
Crospovidone (Kollidon CL)
Colloidal silicon
Pearlitol Flash
Opadry 03F190003Clear
Opadryll 85F19000Clear
" preparaton ratio " mixture is prepared with following compositions: 2.40mg cyclobenzaprine HCl, 31.55mg mannitol and jade Rice starch, 2.00 Crospovidones, 0.50mg colloidal silicon dioxide, 0.050mg sodium stearyl fumarate and 1.05 dipotassium hydrogen phosphates.
The aliquot of API and each excipient is ground with the weighing of 1:1 (unless otherwise specified) ratio in agate mortar.So Post analysis homogeneous mixture.Differential scanning calorimetry (DSC)
DSC heating curves is obtained under the following conditions with TA 821DSC Mettler equipment:
The rate of heat addition: l0 DEG C/min
Environment: nitrogen 30mL/min
Specimen holder: common opening aluminium dish
Temperature range: 25 DEG C to 250 DEG C
Equipment Alignment: indium sample purity 99.999%
For individual cyclobenzaprine HCl, detects that fusing is decomposed at 210 DEG C to 223 DEG C and (start at 215.2 DEG C, Δ H =-96.5J/g) (Fig. 1).
In the 1:1 mixture of cyclobenzaprine HCl and sodium stearyl fumarate, the endothermic transition of sodium stearyl fumarate is 100 DEG C (Fig. 2) is recorded to 120 DEG C.API transition peak is not detected, it has been observed that Physical interaction.
In the 1:1 mixture of cyclobenzaprine HCl and sodium stearyl fumarate, sodium stearyl fumarate endothermic transition is at 90 DEG C (Fig. 3) is recorded to 120 DEG C.Detect that API transition peak (starts from 202.31 DEG C, Δ H=-50.5J/ at 192 DEG C to 216 DEG C g).Observe slight Physical interaction.In the case where the rising of possible temperature can induce API to change, the phase interaction With during being likely to occur in tablet press.
In the 1:1 mixture of cyclobenzaprine HCl and potassium hydrogen phosphate, observed between API and excipient chemical mutual It acts on (Acid-Base).Observe 40 DEG C to 60 DEG C of transformation (Fig. 4), in addition API melting hump is slightly visual at high temperature.
In preparaton ratio, peak is observed at 47 DEG C, it may be possible to since water is by K2HPO4It absorbs, in addition extremely at 182 DEG C 210 DEG C detect API melting hump (starting from 195.6 DEG C, Δ H=-31.4/g) (Fig. 5).Slight phase is observed in higher temperature Interaction.
In the 1:1 mixture of cyclobenzaprine HCl and Crospovidone (Kollidon CL), the release of water is infiltrated at 30 DEG C It is recorded to 110 DEG C, fusing/decomposition of subsequent API is recorded at 210 DEG C to 223 DEG C (starts from 214.4 DEG C, Δ H=- 37.4J/g) (Fig. 6).Interaction is not detected.
In the 1:1 mixture of cyclobenzaprine HCl and silicon (colloid), API fusing/decomposition peak remembers at 186 DEG C to 221 DEG C Record and (start from 207.2 DEG C, Δ H=-41.4J/g) (Fig. 7).Interaction is not detected, there is only crystallinity reductions.
In cyclobenzaprine HCl and Pearlitol1:1 mixture, surprisingly at 130 DEG C to 168 DEG C Observe that physical complexes interact peak (eutectic mixture) (starting from 143.2 DEG C, Δ H=-151.8J/g) (Fig. 8). API transformation fusing is not detected, only there are physical complexes fusions in lower temperature.
In preparing agent composition, because ratio is about 13:1: API,It is molten Change peak and detect and (start from 162.0 DEG C, Δ H=-172.2 J/g) (Fig. 9) at 150 DEG C to 173 DEG C, in 137 DEG C to 151 DEG C elder generations Occur small peak (starting from 142.2 DEG C, Δ H=-12.2J/g), reason is the eutectic mixture between two components.In 1:1 Identical behavior is observed in mixture.
In the 1:1 mixture of cyclobenzaprine HCl and Opadry Clear, PEG transformation is easily seen at 46 DEG C to 64 DEG C It observes, subsequent API fusing/decomposition peak observes at 180 DEG C to 218 DEG C and (start from 199.0 DEG C, Δ H=-45.5J/g) (figure 10).Interaction is the Opadry due to fusing.
In the 1:1 mixture of cyclobenzaprine HCl and Opadry II Clear, PEG transformation is easy at 44 DEG C to 65 DEG C Observe that then the interaction peak between PVA (polyvinyl alcohol) and API is observed to 213 DEG C at 44 DEG C and (started from ground 154.9 DEG C, Δ H=-32.5Jig) (Figure 11), this can be since API is by excipient partial salvation.
In preparing agent composition, an incident heat is only recorded at 124 DEG C to 170 DEG C and (starts from 157.0 DEG C, Δ H =-164.1Jig) (Figure 12).The event is PearlitolCaused, reason is that its scale is blinded by whole Other transformations.In addition, API and Pearlitol generates eutectic mixture (solid-state physics interaction), detected at 142 DEG C It arrives.The Physical interaction can stabilize preparaton and prevent with excipient (such as Opadry I, Opadray II and K2HPO4) other interactions.
In order to evaluate the interaction between API and excipient, for 40 DEG C and 50 DEG C store 1 month tablet into Row heat research.By the data of record compared with the thermal characteristics for the same batch analyzed in time zero.Cyclobenzaprine HCl is recorded To two incident heats: first event is the mishap at 146.0 DEG C, and second event (is started from 136 DEG C to 170 DEG C 158.3 DEG C, Δ H=-143.2 J/g) (Figure 13), the mainly fusing due to Pearlitol Flash.
Be recorded two incident heats at 40 DEG C to cyclobenzaprine HCl: first is small individual at 145.8 DEG C, and second A is at 134 DEG C to 171 DEG C (starting from 156.7 DEG C, Δ H=-169.7J/g) (Figure 14), mainly due to PearlitolFusing.Also be recorded two incident heats at 50 DEG C to cyclobenzaprine HCl: first is in small of 146.5 DEG C Body and second be at 137 DEG C to 179 DEG C (starting from 158.4 DEG C, Δ H=-163.3J/g) (Figure 15), mainly due to Pearlitol Fusing.The thermal behavior of record is similar, and the tablet after 40 DEG C and 50 DEG C storages In do not observe interaction.The interaction to binary mixture record is not observed again, it may be possible to due to API quilt PearlitolFiguration dilution agent and between API and lubricant sodium stearyl fumarate reduction contact.
On the whole, different types of interaction is observed between excipient and API.Sodium stearyl fumarate is seen Observe Physical interaction, especially 1:1 ratio, it may be possible to due to the API solvation of part or in particle surface Cl-With Na+ Reaction between ion balance.In preparaton ratio, which disappears.Even continue to test for 1 month at 40 DEG C and 50 DEG C In the preparaton of stability, the interaction is not observed yet.Chemical (Acid-Base) interaction is observed to potassium hydrogen phosphate, It is 1:1 and preparaton ratio.Interaction is not observed to silicon (colloid) and Kollidon.To Pearlitol Observe that eutectic interacts, reason is that there are mannitol.In preparaton ratio (about 13:1 excipient: API), API Heat deflection be displaced completely by the formation (eutectic mixture) of excipient compound.With the phase interaction of Opadry Clear It with smaller, and is due to the PEG contribution before API transformation.It is obvious with the interaction of Opadry II Clear, and It can be since there are the PVA of partial salvation API (polyvinyl alcohol).Table 1 summarizes the various taxes to cyclobenzaprine HCl API The observation of shape agent.
Table 1: it is reacted with the excipient of API
ND: undetermined
Embodiment 2
As described above, thermoanalysis technology is also used to evaluate the drug products (tablet) containing cyclobenzaprine HCl (API) Compatibility.Compatibility Evaluation is carried out with 1:1 ratio between API and additional excipients.1:1API- excipient mixture with Two kinds of different modes are formed: first, only by mixing and second, pass through strong grinding in the agate mortar.It will be to two kinds not Compared with those of thermal behavior and one-component with mixture record.Based on to each component and to mixture record incident heat, It is analyzed by the peak meaning of mixture record of research differential scanning calorimetry (DSC) between API and excipient. In addition, being carried out to define the property of interaction to certain samples (mixture of API, excipient and mixing and grinding) Fourier transform infrared spectroscopy is totally reflected (FT-IR/ATR) and X-ray powder diffraction (XRPD) with decaying and is compared.
Using following raw materials:
Cyclobenzaprine HCl
Anhydrous dibasic sodium phosphate
Disodium hydrogen phosphate dihydrate
Disodium hydrogen phosphate heptahydrate
Citric acid trisodium dihydrate
Sorbierite
Mannitol
Mix API+ anhydrous dibasic sodium phosphate
Mix API+ disodium hydrogen phosphate dihydrate
Mix API+ disodium hydrogen phosphate heptahydrate
Mix API+ citric acid trisodium dihydrate
Mix API+
Mix API+ sorbierite
Mix API+ mannitol
Anhydrous citric acid sodium
Glycine carbonic acid disodium
Mix API+ anhydrous citric acid sodium
Mix API+ glycine carbonic acid disodium
The aliquot of API and each excipient is ground with ratio 1:1 weighing in agate mortar.Then, analysis homogeneous is mixed Close object.These sample mixtures are labeled as " B ", and only the mixture of machinery is labeled as " A ".
Differential scanning calorimetry (DSC)
DSC heating curves is obtained under the following conditions with TA 821DSC Mettler equipment:
The rate of heat addition: 10 DEG C/min
Environment: nitrogen 30mL/min
Specimen holder: common opening aluminium dish
Temperature range: 25 DEG C to 250 DEG C
Equipment Alignment: indium sample purity 99.999%
Fourier transform infrared spectroscopy and decaying total reflection (FT-IR/ATR)
FT-IR spectrogram is obtained with Perkin Elmer spectrum Two equipment, with air as background and 4cm-1It differentiates Rate.
X-ray powder diffraction (XRPD)
X-ray powder diffraction (XRPD) test is carried out with ULTIMA IV equipment (Rigaku), and sample is placed on static state Specimen holder.X-ray focusing slit has variable-width, interlocks with q value.X-ray tube have copper palladium, current strength be 40mA and Voltage is 40kV.Radiation is generated by Cockcroft-Walton method, and including Kα1 And Kα2 Analysis condition is:
Regular time；Sampling width is 0.02deg, and sweep speed is 1.3s/ step, 2q range 3.35deg and sample Frame；Amorphous glass isogonism 9200/2G, 0.2mm are deep.Sample is squeezed with glass plate.
Cyclobenzaprine HCl, which is detected with fusing decomposition at 210 DEG C to 225 DEG C, (starts from 215.6 DEG C, Δ H=- 105.0J/g) (Figure 16).The DSC heating curves for comparing mixture and API and excipient (mixture A and B), is then analyzed.1: The interaction peak of 1 cyclobenzaprine HCl- anhydrous sodium phosphate mixture (mixture A) is recorded at 167 DEG C to 220 DEG C (to be started In 197.0 DEG C, Δ H=-109.6 J/g).It observes Physical interaction, is characterized as the reduction (Figure 17) of API fusing.1:1 ring The interaction peak that benzene pricks woods HCl- anhydrous sodium phosphate mixture (mixture B), which is recorded at 172 DEG C to 201 DEG C, (to be started from 180.9 DEG C, Δ H=-31.1J/g).Observe Physical interaction (Figure 18).By comparing mixture A and B, it is apparent that Interaction shows more (Figure 19) in the mixture of grinding.
The crystallization water is from sodium phosphate in the 1:1 mixture of cyclobenzaprine HCl and sodium phosphate dihydrate (mixture A) Release observed at 57 DEG C to 108 DEG C and (start from 73.4 DEG C, Δ H=-227.8 J/g), then interact peak at 174 DEG C extremely 220 DEG C are observed (Figure 20).The effect is made of two kinds of small effects: Physical interaction and partial solvation.It is several on the diagram Peak is not observed, it may be possible to since a small amount of water is released into the matrix of fusing.The crystallization water is from cyclobenzaprine HCl and phosphorus The release of sour sodium dihydrate (mixture B) 1:1 mixture is recorded at 61 DEG C to 100 DEG C (starts from 71.8 DEG C, Δ H=- 239.8J/g), then interaction peak is recorded at 160 DEG C to 221 DEG C and (starts from 178.7 DEG C, Δ H=-116.5J/g) (Figure 21).Observe Physical interaction.Figure 22 is shown in mixture A compared between B.The milled mixtures the case where Lower interaction becomes apparent from.
Water energy present in excipient reaches modified mixture and reduces API stability.
The crystallization water from the release of cyclobenzaprine HCl and sodium phosphate heptahydrate (mixture A) 1:1 mixture (not with two Same step) in 39 DEG C to 68 DEG C (starting from 47.2 DEG C, Δ H=-77.6J/g) and 67 DEG C to 96 DEG C (start from 73.8 DEG C, H =-68.9J/g) it is recorded, the peak that then interacts is recorded at 176 DEG C to 220 DEG C (starts from 199.5 DEG C, Δ H=- 83.4J/g) (Figure 23).For mixture B, the crystallization water (with two different steps) 43 DEG C to 54 DEG C (start from 45.9 DEG C, Δ H=-49.6J/g) and 73 DEG C to 98 DEG C (starting from 77.8 DEG C, Δ H=-151.7J/g) releases, then interact peak At 174 DEG C to 215 DEG C (starting from 174.5 DEG C, Δ H=-55.4J/g) (Figure 24).Figure 25 is shown between mixture A and B Compare.It is estimated in milled mixtures to interact and show two events, it is related to interact peak and remnants API.Figuration Water present in agent induces API physical change, or even also such in low temperature.
The crystallization water is from cyclobenzaprine HCl and the release of citric acid trisodium dihydrate (mixture A) 1:1 mixture and decomposes (complex spike) is recorded at 154 DEG C to 183 DEG C and (starts from 167.1 DEG C, Δ H=-127.6J/g), and the peak that then interacts exists 186 DEG C to 227 DEG C are recorded and (start from 197.2 DEG C, Δ H=- 102.6J/g) (Figure 26).Observe physical chemistry phase interaction With.The
Crystallization water release and excipient decompose (complex spike) and are recorded at 146 DEG C to 181 DEG C and (start from mixture B 157.9 DEG C, Δ H=-179.4J/g), the peak that then interacts is recorded at 180 DEG C to 216 DEG C (starts from 190.5 DEG C, Δ H =-88.7J/g).Observe that physical chemistry interacts (Figure 27).The decomposition of citric acid trisodium is phase in mixture A and B As (Figure 28).
In 1:1 cyclobenzaprine HCl-The release CO of mixture (mixture A)2Remember at 99 DEG C to 187 DEG C It records and (starts from 109.5 DEG C, Δ H=-308.0J/g), subsequent API, which is melted in 193 DEG C and is recorded to 218 DEG C, (to be started from 203.2 DEG C, Δ H=-46.8J/g) (Figure 29).The Physical interaction observed is smaller, but since excipient is unstable Property；It is expected that API melting hump and interacting.Mixture B causes 104 DEG C to 210 DEG C (to start from 132.9 DEG C, Δ H=- 399.6 J/g) CO2Release and the peak API disappear (Figure 30).Observe that physical chemistry interacts.In relatively mixture A and B In, the interaction of mechanical impurity is lower, and milled mixtures is then higher.In addition,Discharge CO2It covers API behavior is covered, reason is possible interaction (Figure 31).
In the 1:1 mixture of cyclobenzaprine HCl and sorbierite (mixture A), sorbierite fusing masking API melting hump. Event is recorded at 81 DEG C to 108 DEG C and (starts from 96.7 DEG C, Δ H=-88.2 J/g) (Figure 32).Observe interaction, it is former Because being API by sorbierite solvation.For mixture B, API melting hump is also sheltered in sorbierite fusing.Event at 82 DEG C extremely 107 DEG C are recorded and (start from 95.3 DEG C, Δ H=-87.3J/g) (Figure 33).Observe interaction, reason is API quilt Sorbierite solvation.Interaction is analogous (Figure 34) in mixture A and B.In order to confirm sorbierite in the mixture phase Between solvation API, carry out XRPD investigation (Figure 35).Mixture shows several sorbierite peaks and seldom peak cyclobenzaprine HCl. Baseline broadening instruction amorphous phase, reason is ma trix melting.
Surprisingly, (starting in 1:1 cyclobenzaprine HCl- mannitol mixture (mixture A) at 137 DEG C to 170 DEG C In 147.3 DEG C, Δ H=-164.6J/g) observe that physical complexes interact peak (eutectic mixture) (Figure 36).It does not examine API transformation fusing is measured, only eutectic mixture is melted in lower temperature.For mixture B, (start at 132 DEG C to 167 DEG C In 141.5 DEG C, H=-153.4J/g) (Figure 37) also observe that physical complexes interact peak (eutectic mixture).Not Detect API transformation fusing, only eutectic mixture is melted in lower temperature.Interaction is comparable in two kinds of mixtures Quasi- (Figure 38).
In the 1:1 mixture of cyclobenzaprine HCl and anhydrous citric acid sodium (mixture A), the peak that interacts is at 168 DEG C (Figure 39) is observed to 215 DEG C (starting from 188.8 DEG C, Δ H=-102.4J/g).API transformation fusing is not detected, only physics Compound is melted in lower temperature.In mixture B, the peak that interacts (starts from 167.7 DEG C, H=- at 158 DEG C to 211 DEG C 110.1J/g) observe (Figure 40).API transformation fusing is not detected, only physical complexes are melted in lower temperature.Comparing When grinding and mixed mixture, interaction becomes apparent from (Figure 41) in milled mixtures.
In the 1:1 mixture of cyclobenzaprine HCl and glycine carbonic acid disodium (mixture A), wide interaction peak exists 155 DEG C to 231 DEG C (starting from 180.7 DEG C, H=-79.3J/g) are observed (Figure 42).API transformation fusing is not detected, only object Compound is managed to melt in lower temperature.Mixture B is generated 155 DEG C to 231 DEG C (starting from 184.0 DEG C, H=-77.0J/g) Interaction peak (Figure 43).API transformation fusing is not detected, only physical complexes are melted in lower temperature.It is mixed at two kinds Closing interaction in object is analogous (Figure 44)
FT-IR/ATR
In order to define the property for the interaction that DSC is observed and whether understand the heat treatment during temperature rises It is to carry out the investigation of FT-IR/ATR spectrum the reason of leading to different DSC features.In Figure 45-47, cyclobenzaprine HCl and anhydrous The FT-IR/ATR spectrogram of sodium citrate (mixture A) is overlappingly shown in the different areas.In the mixture, API is observed Occur with whole bands of a spectrum of excipient.Especially, in 3000-2000cm-1Region (Figure 45), hydrogen chloride band is still visual, refers to Show that having no chemical Acid-Base reaction occurs.In Figure 48, the overlapping of mixture A and B, which are shown, does not observe material change.
Figure 49-51 shows the FT-IR/ATR spectrogram of cyclobenzaprine HCl and glycine carbonic acid disodium (mixture A), not With being overlapped in region.In the mixture, whole bands of a spectrum of API and excipient are observed.Especially, in 3000-2000cm-1Area Domain (Figure 49), hydrogen chloride band is still visual, and instruction has no chemical Acid-Base reaction and occurs.Figure 52 describes the weight of mixture A and B It is folded.Do not observe material change.From FT-IR/ATR spectrogram it is found that the heat deflection of record is originated from heating mixture, but in room The lower two kinds of components of temperature are stable and noninteracting.
On the whole, different types of interaction is observed in excipient and API.For whole basic excipients It studies (especially hydrate), observes interaction.Interaction seemingly acid/base type reaction, it may occur however that sun from Between sub- Na and the HCl of drug substance.Interaction is more significant in milled mixtures, reason be API and excipient it Between particle contact it is deeper and more closely.Physical interaction is observed for sorbierite, reason is API in fusing figuration Solvation in agent；And for mannitol, it has been surprisingly observed that the formation of eutectic mixture.With anhydrous citric acid trisodium With glycine carbonic acid disodium interaction be only physics and higher temperature occur when, as shown in FT-IR/ATR spectrum.Table 2 It is shown in the summary of the interaction between API and excipient, including the mixture for mixing and grinding.
Table 2: the interaction between cyclobenzaprine HCl and excipient
Embodiment 3
The compatibility of mannitol and cyclobenzaprine HCl are studied by differential scanning calorimetry (DSC), and evaluation gained is mutually Effect.Especially, improve between mannitol and cyclobenzaprine HCl in mixing periods formation eutectic mixture intergranular The more preferably physics knot of cohesive force and offer between cyclobenzaprine HCl active pharmaceutical ingredient (API) and mannitol excipient It closes.Extraly, physical state prevents cyclobenzaprine form of administration to be etched.
In cyclobenzaprine HCl and PearlitolInteraction between (excipient containing mannitol) is Constant Physical interaction, reason are that it is in thermal balance, and two of them component is able to be sufficiently mixed and stabilize. Physically, this mean the eutectic mixture of fusing, solid eutectic and solid mannitol all and meanwhile coexist and In chemical balance.Solid macrostructure derived from eutectic reaction depends on several factors, including two kinds of solid solutions are in machine Tool mixing periods are nucleated and grow together.
Because mannitol is the usual excipients in solid pharmaceutical formulation, check that it is compatible with cyclobenzaprine HCl Property, it is studied with DSC, and evaluate the interaction of generation.Surprisingly, finding eutectic mixing during mechanical mixture The formation of object.In order to confirm the formation of eutectic mixture and characterize its physical characteristic, the API and figuration of different ratios are prepared Several binary mixtures of agent, and analyzed by DSC and XRPD.The formation of eutectic mixture improves API and figuration Cohesive force between agent particle, and ensure between both more preferably physical bond.
In order to confirm eutectic mixture formation and characterize its physical characteristic, the number of different ratio A PI- excipient is prepared Kind binary mixture, passes through DSC and X-ray powder diffraction (XRPD) is analyzed.Pass through mild abrasive particles in the agate mortar Cyclobenzaprine HCl and mannitol obtain mixture, to obtain the homogeneous distribution of particle.For each DSC heating curves, Eutectic mixture is contributed and all evaluates initial temperature and enthalpy to component is excessive.Record value is mapped, two components are obtained Between phasor, with eutectic mixture phasor indicatrix.
Mixture is studied also by XRPD, and with pure component trace analysis.These analyses are carried out to confirm that eutectic is multiple Closing object is only the Physical interaction between two kinds of products, rather than forms the new individual of different chemical characteristics.It will be to mixing The XRPD map that object obtains is mapped with pure component compared with to confirm the linear of mannitol and cyclobenzaprine HCl peak intensity (cpf), With the proportional peak height at 2 angle θ of feature.
The aliquot of cyclobenzaprine HCl API and mannitol is weighed with the ratio being described as follows, and is ground in agate mortar It is broken, and with post analysis homogeneous mixture.
9 90
10 95
Differential scanning calorimetry (DSC)
DSC heating curves is obtained under the following conditions with TA 821DSC Mettler equipment:
The rate of heat addition 10℃/min
Environment Nitrogen, 30mL/min
Specimen holder Common opening aluminium dish
Temperature range 25 DEG C to 250 DEG C
Equipment Alignment Indium sample purity 99.999%
X-ray powder diffraction (XRPD)
X-ray powder diffraction (XRPD) test is carried out with ULTIMA IV (Rigaku) equipment, and sample is placed on static state On specimen holder.X-ray focusing slit has variable-width, interlocks with θ value.X-ray tube has copper palladium, current strength 40mA It is 50kV with voltage.The radiation that Cockcroft-Walton method generates includes Kα1 And Kα2 Analysis condition is as follows:
Set time: sampling width, 0.02deg；Sweep speed, 1.0s/ step
2 θ ranges: 3/50deg.
Specimen holder: amorphous glass-isogonism 9200/2G, 0.2mm is deep.Sample is squeezed with glass plate.
The pure component and the two mixture of cyclobenzaprine HCl and mannitol are with dsc analysis (table 1).Figure 53 description The fusion curve of 100% cyclobenzaprine HCl.210 DEG C to 221 DEG C, which are melted in, with decomposition (starts from 215.5 DEG C, Δ H=- 100.6J/g) detect.Figure 54 describes the fusion curve of 100% mannitol.It is melted in 151 DEG C to 173 DEG C and (starts from 164.4 DEG C, Δ H=-256.8J/g) it detects.Figure 55-64 describes various mixtures.3 summary data of table.
Table 3:DSC outline data
The above results, which are shown, forms eutectic mixture group in about 75% cyclobenzaprine HCl (API) and 25% mannitol Close object.75% hereinafter, being melted in eutectic mixture fraction different with observing two in the excessive situation of independent component Melting hump.Figure 65 shows phasor, describes the beginning fusion temperature of eutectic fraction and excess component, the letter as API percentage Number mapping.5 different zones appear in figure: region A: mannitol is excessive (liquid eutectic mixture+solid mannitol)
Region B: cyclobenzaprine HCl is excessive (liquid eutectic mixture+solid cyclobenzaprine HCl)
Region C: solid eutectic and mannitol
Region D: solid eutectic and cyclobenzaprine HCl
Region E: liquid phase and mannitol and cyclobenzaprine HCl
In region a, in the increased situation of API percentage, the initial temperature of excessive mannitol is reduced, and eutectic About 143 DEG C of the temperature holding of mixture fraction is constant.On eutectic mixture composition, excessive API causes temperature to increase (region B).In addition, good related between mixture and temperature.It is due to not exclusively from several little deviations of trend curve The mixture of powders of matter.
Figure 66 shows eutectic melting enthalpy, is the function of API percentage.Eutectic melting enthalpy is increased up the low of acquisition Eutectic mixture composition.Maximum value should be reached in the case where eutectic mixture composition, but due to the part of product point Solution, it is impossible to correctly evaluation fusing heat.On the contrary, display is based on pure compound fusion enthalpy theoretical value obtained in figure.It is low total Molten mixture composition corresponds to 75%API, and 25% mannitol is by weight.Theoretical ratio (311.38 between molecular weight It mw/182.17mw) is 1.71, and what the ratio [(0.75/311.38mw)/(0.25/182.17mw)] of weight percent provided Eutectic molar ratio is 1.76 (the corresponding 1 mole of mannitol of 1.76 moles of cyclobenzaprine HCl i.e. in eutectic mixture).
XRPD
It is physical mixture and not formed new individual or adduct to confirm eutectic mixture composition only, leads to X-ray powder diffraction analysis of mixtures is crossed, wherein not applying heat treatment (pure cyclobenzaprine HCl, Figure 67-68；Pure mannitol, Figure 69-70).Figure 71 describes the overlapping of pure mannitol, API and the eutectic mixture in 75%, shows different diffraction zones, In and cannot be distinguished from pure component peak and interference is not detected.Figure 72 shows the overlapping of pure mannitol and API and its mixture, It can wherein can designate that 3 different range of diffraction: mannitol 14.1-15.0 ° of 2 θ, 2 θ of API 12.5-13.3 ° and 17.5-18.2 ° 2 θ.Within the scope of these, (30,50,65,75 and 90%) are evaluated to each mixture analyzed.Each peak height is as API% Function construction, obtain linear coefficient (Figure 73-74).Obtain the good correlation between concentration and peak height.API and sweet dew Alcohol does not cause adduct to be formed in the case where mixing, but only physics eutectic mixture is formed.
On the whole, data show that the thermal behavior of mixture shows two endotherms, are related to eutectic mixture and excess The fusing of main component.API/ mannitol percentage present in eutectic mixture is corresponded to the incident heat of mixture record Ratio.In eutectic composition, only one melting hump is visual.Reach eutectic mixing in about 75%API and 25% mannitol Object composition.The eutectic mixture composition confirmation molar stoichiometric (ratio of two kinds of components: 1.76).Eutectic mixture Fusion temperature is about 143.6 DEG C, and has record to full-fledged research mixture.Through XRPD, between API and mannitol Adduction interaction does not occur, but only forms physics eutectic mixture.
Embodiment 4
Thermoanalysis technology is used to evaluate the compatibility of drug products amitriptyline HCl.With 1:1 between API and excipient Ratio carries out Compatibility Evaluation.Based on to each component and to the incident heat of mixture record, recorded by research by DSC The peak of the mixture of API and excipient is analyzed.In the agate mortar after abrasive product, obtain in single compound With in relation to the thermal characteristics difference between mixture.
The description that DSC substantially presses Examples 1 and 2 carries out.Using following raw materials:
Amitriptyline HCl
Sodium stearyl fumarate
Stearic acid
Dibehenolin
Magnesium stearate
Pearlitol Flash
Pearlitol 200SO/ mannitol
The cornstarch of Unipure DW/ pregelatinated
Crospovidone-Kollidon CL
Colloidal silicon/aerosil 200
Dibastic sodium phosphate
Sodium bicarbonate
Sodium carbonate
Sodium phosphate dodecahydrate
Anhydrous sodium phosphate.
The fusing and decomposition of 100% amitriptyline HCl (starts from 195.1 DEG C, Δ H=- at 192 DEG C to 202 DEG C 93.9J/g) detect (Figure 75).
In the 1:1 mixture of amitriptyline HCl and sodium stearyl fumarate, the endothermic transition of sodium stearyl fumarate is 90 DEG C (Figure 76) is recorded to l20 DEG C.API transformation peaks are not detected, and observe Physical interaction.
Stearic endothermic transition in amitriptyline HCl and stearic 1:1 mixture is recorded at 47 DEG C to 64 DEG C It arrives.API transformation peaks detect (Figure 77) 179 DEG C to 195 DEG C (starting from 181.1 DEG C, Δ H=- 5.15J/g).It observes light Microphysical interaction.
In the 1:1 mixture of amitriptyline HCl and dibehenolin (or Gan You behenic acid ester), two mountain of glycerol The endothermic transition of Yu acid esters is recorded at 63 DEG C to 74 DEG C.API transformation peaks (start from 189.0 DEG C, Δ H at 186 DEG C to 199 DEG C =-3l.0J/g) detect (Figure 78).Observe that light physical interacts.
In the 1:1 mixture of amitriptyline HCl and magnesium stearate, the endothermic transition of magnesium stearate is at 100 DEG C to 120 It DEG C is recorded.API transformation peaks detect (Figure 79) 169 DEG C to 187 DEG C (starting from 174.0 DEG C, Δ H=-10.6J/g).It sees Observe light physical interaction.
In amitriptyline HCl and Pearlitol1:1 mixture in, the excipient containing mannitol, physics Compound interaction peak (eutectic mixture) observes (Figure 80) at 130 DEG C to 170 DEG C.It is molten that API transformation is not detected Change, only in lower temperature, there are physical complexes fusions.Eutectic mixture fusing point corresponds to 135.1 DEG C (initial value) (figures 81)。
In the 1:1 mixture of amitriptyline HCl and Pearlitol 200SD/ mannitol, physical complexes phase interaction (Figure 82) is observed at 130 DEG C to 170 DEG C with peak (eutectic mixture).API transformation fusing is not detected, only compared with low temperature There are physical complexes fusions for degree.Eutectic fusing point corresponds to 132.8 DEG C (initial value) (Figure 83).With contain only Pearlitol The mixture of Flash compares about 2 DEG C of fusion temperature difference, is due to there is additional mannitol in the mixture.
Infiltrate water releasing in amitriptyline HCl and Unipure DW/ cornstarch (part pregelatinated) 1:1 mixture It is placed on 30 DEG C to 110 DEG C to be recorded, subsequent API's is melted in 178 DEG C to 199 DEG C and (starts from 181.9 DEG C, Δ H=-28.2J/ G) (Figure 84) is recorded.Interaction is not detected
In the 1:1 mixture of amitriptyline HCI and Crospovidone (Kollidon CL), the release of water is infiltrated at 30 DEG C It is recorded to 100 DEG C, fusing/decomposition of subsequent API is 192 DEG C to 200 DEG C (starting from 194.4 DEG C, Δ H=-41.3J/g) (Figure 85) is recorded.Interaction is not detected.
In the 1:1 mixture of amitriptyline HCl and silicon (colloid), API melting hump (starts from 188 DEG C to 200c DEG C 193.7c DEG C, Δ H=-17.2J/g) (Figure 86) is recorded.Interaction is not detected, only crystallizes the degree of amitriptyline HCl It reduces.
The endothermic transition of dibastic sodium phosphate in the 1:1 mixture of amitriptyline HCl and dibastic sodium phosphate is in 60 DEG C and 80 DEG C It is recorded.API transformation peaks detect (Figure 87) in 180 DEG C and 193 DEG C.
In the 1:1 mixture of amitriptyline HCI and sodium bicarbonate, the endothermic transition of sodium bicarbonate is at 150 DEG C to 180 DEG C (Figure 88) is recorded.API transformation peaks are not detected.Observe Physical interaction.
In the 1:1 mixture of amitriptyline HCl and sodium carbonate, the endothermic transition of sodium carbonate is recorded at 70 DEG C to 90 DEG C To (Figure 89).API transformation peaks are detected 180 DEG C to 197 DEG C (starting from 182.8 DEG C, Δ H=-33.8J/g).It observes light Microphysical interaction.
In the 1:1 mixture of amitriptyline HCl and sodium phosphate dodecahydrate, endothermic transition is remembered at 40 DEG C to 1l2 DEG C Record (Figure 90).API transformation peaks are not detected.Observe that physical/chemical interacts.
The endothermic transition of amitriptyline HCl and the sodium phosphate in anhydrous sodium phosphate 1:1 mixture is recorded at 40 DEG C to 90 DEG C It arrives.API transformation peaks detect (Figure 91) 174 DEG C to 192 DEG C (starting from 179.8 DEG C, Δ H=-222.8J/g).It observes Physical interaction.
On the whole, different types of interaction is observed in excipient and API.To magnesium stearate and phosphoric acid hydrogen Sodium observes that Physical interaction, possible cause are part API solvation.To Pearlitol Flash and Pearlitol 200SO/ mannitol observes that eutectic interacts, and reason is that there are mannitol.The heat deflection of API is by the tax of eutectic The formation of shape agent compound is moved completely.Physical interaction, possible cause, which are part, to be observed to sodium stearyl fumarate API solvation or particle surface HCl are reacted with Na ion balance.Physics phase interaction is observed to sodium phosphate dodecahydrate With, it is also possible to because of part API solvation.To stearic acid, dibehenolin, the part Unipure DW/ pregelatinated Cornstarch, silicon (colloid), Crospovidone/Kollidon CL, sodium carbonate, sodium bicarbonate or anhydrous sodium phosphate do not observe phase Interaction.Table 4 summarizes the data observed.
Table 4: the interaction between API and excipient
Excipient Mixture (1:1 ratio) in preparaton
Sodium stearyl fumarate Physical interaction
Stearic acid Without interaction
Dibehenolin Without interaction
Magnesium stearate Physical interaction
Pearlitol Flash Eutectic interaction
Pearlitol 200SO/ mannitol Eutectic interaction
The cornstarch of Unipure DW/ pregelatinated Part is without interaction
Crospovidone-Kollidon CL Without interaction
Colloidal silicon/aerosil 200 Without interaction
Dibastic sodium phosphate Physical interaction
Sodium bicarbonate Without interaction
Sodium carbonate Without interaction
Sodium phosphate dodecahydrate Physical interaction
Anhydrous sodium phosphate Without interaction
Embodiment 4
In order to test whether the wet-mixing of cyclobenzaprine and mannitol changes eutectic mixture, 10g eutectic is mixed It closes object (75%API and 25% mannitol) and 1mL water is placed in mortar, mixing is until reach paste consistency.At room temperature should Paste places drying, while grinding in mortar.The sieving mill pulverized powder in 500 μm of sieves.Sample morphology passes through scanning electricity Sub- microscope (SEM) FEI S50 appraisal of equipment, wherein electron beam is accelerated by 25kV voltage, is carried on bonding graphite plate And it is coated with layer gold.Specific surface area (SSA) and powder porosity are evaluated by BET method (nitrogen), in Micromeritics Sample is set to deaerate under nitrogen 2 hours at 40 DEG C in 3020 equipment of Tristar II.DSC heating curves passes through TA 821DSC Mettler equipment obtains under the following conditions:
X-ray powder diffraction (XRPD) test is carried out with ULTIMA IV equipment (Rigaku), and sample is placed on static state On specimen holder.X-ray focusing slit has variable-width, interlocks with θ value.X-ray tube has copper palladium, current strength 40mA The radiation generated with voltage for 50kV and Cockcroft-Walton method includes Kα1 And Kα2 Analysis condition is as follows:
Regular time
Sampling width: 0.02deg
Sweep speed: 1.0s/ step
2 θ ranges: 3 ÷ 50deg.
Specimen holder: amorphous glass-isogonism 9200/2G, 0.2mm is deep.Sample is squeezed with glass plate.
SEM, which is shown, is formed by the particle that eutectic mixture has hard surface by wet granulation, as shown in Figure 92. Compared with the particle that these particles can be observed with the SEM of pure cyclobenzaprine HCl (Figure 93) and pure mannitol (Figure 94).Measurement Physical features are simultaneously summarized in table 5 (SSA: specific surface area；The particle of D10:10% is less than the measurement；The particle of D50:50% is small In the measurement；The particle of D90:90% is less than the measurement).Figure 95 describes the particle size of the eutectic mixture of wet granulation Distribution and Figure 96 describe the eutectic mixture pore volume vs diameter of wet granulation.In addition, DSC and X-ray powder diffraction are aobvious Show that mannitol mixes in eutectic mixture composition (Figure 97 and Figure 98, respectively) completely.
Table 5: the physical features for the eutectic mixture that wet granulation is formed
Embodiment 5
Other than wet-mixing, spray drying can also be used to mix each ingredient to prepare pharmaceutical composition.By sweet dew 5 kinds of mixtures (10g) of the different ratios of pure and mild cyclobenzaprine HCl are dissolved in 500ml water, for being spray-dried.Total solid concentration It is 2%w/v, although 15%w/v is also used in previous test (data are not shown).With Bu chi spray dryer B-290 (Bu chi Labortechnik, Flawil, Switzerland) spray drying soln under conditions of table 6 is reported.In preparation the first two Soft particle is obtained in the case where batch, but other batches have light yellow scale and crystal.Yield obtained is pricked with ring benzene Percentage of the woods HCl in solution to be spray dried increases and reduces.
Table 6: spray-drying process parameter
DSC display spray drying cyclobenzaprine HCl- mannitol mixture unexpectedly mixes the eutectic of mannitol It closes object and is converted into its δ form from its beta form.Mannitol can be crystallized with 3 kinds of polymorphic forms: α, β and δ.This 3 kinds of forms Difference can be X-ray powder diffraction and the different melting points based on each polymorph.See, for example, Sharma and Kalonia, AAPS PharmaSciTech 5(1):E10(2004).In the above-described embodiments, mannitol used is beta-polymorph sweet dew Alcohol.In order to test whether spray-drying process itself is enough to convert δ mannitol from β mannitol for mannitol, to spray drying β mannitol carry out SEM and DSC.The mannitol of Figure 99 and Figure 100 display spray drying seems different from pure mannitol, still DSC discloses individually spray drying and is not sufficient to convert β mannitol to δ mannitol (Figure 101).This is corresponding to spray drying The early stage of mannitol is studied.See, for example, Hulse et al., Drug Development and Industrial Pharmacy 35 (6): 712-718 (2009).It is without being bound by theory, the change of mannitol polymorphic forms seem to come from that spray drying and The combination of cyclobenzaprine is added.This can be because spray drying, different from wet process or dry mixed, and it is right to involve dissolved constituent After allow its cocrystallization together.The mixture of DSC test is 25% cyclobenzaprine: 75% mannitol (weight) (Figure 102), 50% Cyclobenzaprine: 50% mannitol (weight) (Figure 103), 75% cyclobenzaprine: 25% mannitol (weight) (Figure 104) and 90% Cyclobenzaprine: 10% mannitol (weight) (Figure 105).These measurements are used to calculate 134 DEG C of fusing point, and generate eutectic The phasor (Figure 106) of blend composition.Will after spray drying the phasor (δ polymorph) that obtains with after blending In the case that the phasor (beta polymorphic form, Figure 65) of acquisition compares, it can clearly be observed that the difference of fusing point.Beta polymorphic form Fusing point be 143 DEG C, and the fusing point of δ polymorph is 134 DEG C.The lower fusing point be it is beneficial, reason is that its help is molten Solution, as described below.The eutectic mixture that the XRPD of pure mannitol and cyclobenzaprine HCl (Figure 107) and spray drying are formed XRPD (Figure 108) cause the formation of δ mannitol compared to also confirmation spray drying.In fact, XRPD map is shown even The level of 10% mannitol, whole mannitol are just with the presence of δ polymorph.
Also the physical characteristic of δ mannitol eutectic mixture is measured, and is described in Table 7 (SSA: specific surface area； The particle of D10:10% is less than the measurement；The particle of D50:50% is less than the measurement；The particle of D90:90% is less than the measurement). The porosity that SEM discloses the particle that spray drying is formed is significantly larger than those of wet granulation formation (Figure 109 and Figure 110).Figure The particle size distribution of 111 description spray drying eutectic mixtures and Figure 112 description are spray-dried eutectic mixture Pore volume vs diameter.Figure 113-116 describes X-ray powder diffraction data.Especially, Figure 113 description comes from mannitol: ring Benzene pricks the X-ray powder diffraction of the sum from cyclobenzaprine HCl of 25%:75% solution (weight) spray drying experiment of woods HCl (2 θ, 8-18 degree).Mark the position at the expectation peak of mannitol beta polymorphic form (" beta form ") and δ polymorph (" δ form "). Figure 114 description come from mannitol: the spray drying experiment of the 25%:75% solution (weight) of cyclobenzaprine HCl and come from ring The X-ray powder diffraction (2 θ, 22-30 degree) of benzene bundle woods HCl.Mark mannitol beta polymorphic form (" beta form ") and δ polymorph The position at the expectation peak of (" δ form ").Figure 115 description comes from mannitol: the 25%:75% solution (weight) of cyclobenzaprine HCl Spray drying experiment, X-ray powder diffraction (2 θ, 8- of cyclobenzaprine HCl and mannitol beta polymorphic form (" beta form ") 19 degree).Spray drying experiment of Figure 116 description from mannitol-cyclobenzaprine HCl 25%:75% solution (weight), The X-ray powder diffraction (2 θ, 22-30 degree) of cyclobenzaprine HCl and mannitol beta polymorphic form (" beta form ").
The physical characteristic of 7: δ mannitol eutectic mixture of table
In order to test the dissolution characteristics of δ mannitol eutectic mixture, dissolving test is existed with 6000 equipment of Copley DIS It is carried out under the conditions of following:
Equipment: USP blade
RPM:50
Medium: pyrophosphoric acid buffer 0.5%pH=4.5 ± 0.05
Additive: methylcellulose 0.3%
Container volume: 300mL
Temperature: 37 ± 0.5 DEG C
Sampling time: 1,2,5,10,20,30 and 60 minute, then sampling per hour was until 6 hours.
Sampling solution is diluted 1 to 50mL, is then existed to 50mL with UV (GBC Cintral 10e) with medium 1 UV analysis is carried out under the conditions of following:
λ max:224nm
Pond: quartzy 1cm
Blank: medium
Figure 117 is shown in the ionization of cyclobenzaprine under different pH.It is apparent that still having free alkali in pH4.5.Trip Do not enter solution, therefore cyclobenzaprine dissolution and not up to 100% from alkali.Mixture (Figure 118) and spray to wet granulation The dry mixture of mist carries out dissolving test (Figure 119 and 120) to test whether δ mannitol eutectic mixture has difference In the dissolution characteristics of β mannitol dissolved product.Figure 119 description is in wet granulation (WG), dry mixed (MIX) and spray drying (SD) the comparison in 6 hours between mixture and individual cyclobenzaprine HCl (API).These experiments show that special It is not during the 1st hour (Figure 120), the composition of spray drying is faster than wet granulation and the composition of dry mixed Dissolution shows the benefit of δ mannitol eutectic mixture.The dissolution of this enhancing be it is beneficial, reason is that it will increase ring Benzene pricks absorption rate of the woods in oral and sublingual preparaton.The 3 weeks accelerated stabilities test even stored in 50 DEG C of furnaces Later, δ mannitol eutectic mixture or stable.In these tests, δ form remains unchanged, and does not observe conversion For beta form (data are not shown).
Based on δ mannitol phenomenon unexpected in cyclobenzaprine eutectic mixture, spray drying be can also be used to The δ mannitol eutectic mixture of preparation and amitriptyline.

Claims (20)

1. pharmaceutical composition, the eutectic mixture comprising mannitol and cyclobenzaprine HCl, wherein the eutectic mixture packet Containing 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol, by weight.
2. the pharmaceutical composition of claim 1, wherein HCl: β-mannitol of cyclobenzaprine molar ratio is 1.76 ± 0.1.
3. the pharmaceutical composition of claim 1, wherein cyclobenzaprine HCl is the cyclobenzaprine HCl of micronized.
4. the pharmaceutical composition of claim 1 also includes basifier.
5. the pharmaceutical composition of claim 4, wherein basifier is K2HPO4。
6. the pharmaceutical composition of claim 4, wherein basifier is Na2HPO4。
7. the pharmaceutical composition of claim 4, wherein basifier is anhydrous citric acid trisodium.
8. the method for preparing the eutectic mixture pharmaceutical composition of any one of claim 1-7, including mixing cyclobenzaprine HCl and β-mannitol or grinding cyclobenzaprine HCl and β-mannitol.
9. method for claim 8, including grinding cyclobenzaprine HCl and β-mannitol.
10. method for claim 9, wherein grinding cyclobenzaprine HCl and β-mannitol in high shear granulator.
11. method for claim 8, including mixing cyclobenzaprine HCl and β-mannitol.
12. the method for claim 11, wherein cyclobenzaprine HCl and β-mannitol are mixed via compression.
13. the method for claim 12, wherein cyclobenzaprine HCl and β-mannitol are compressed via rolling.
14. method for claim 8, wherein cyclobenzaprine HCl is the cyclobenzaprine HCl of micronized.
15. basifier is added including into the low mixture in method for claim 8.
16. the method for claim 15, wherein basifier is K2HPO4。
17. the method for claim 15, wherein basifier is Na2HPO4。
18. the method for claim 15, wherein basifier is anhydrous citric acid trisodium.
19. the pharmaceutical composition of claim 1, wherein the eutectic mixture is melted in 143.6 ± 3 DEG C.
20. method for claim 8, wherein eutectic mixture is melted in 143.6 ± 3 DEG C.
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